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U.S. Department of Health and Human Services

Animal & Veterinary

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Antimicrobial Resistance Activities at FDA by David White, Ph.D., Director

DR. WHITE: Thank you very much, Pat. And it’s a pleasure to be here. I thought what we could do is I could give Mary’s talk and she could give mine. And just throw things around. Or I could do Rob’s and just see -- we have been all working together for so long.

But a pleasure to be here. As Pat said I’ve been involved with this program for a long time. Stepping away for the past two years. And I’m very excited to see the progress that NARMS has made, especially over the last couple of years under Pat’s leadership. And also in collaboration with CDC and USDA. It’s definitely moving in the right future. And this is a great meeting. I appreciate you all taking the time to come.

So, as Pat mentioned I want to give you a kind of a heads up on how NARMS fits into the CVM strategy because this is not our only component of the resistance strategy that we have at CVM. It fits in very nicely to what we’re trying to do to assure the prudent use of antimicrobials and in particular food animals.

(Slide)

So a lot of you might of know the resistance it waxes and wains. Right now we’re on the high point. We definitely have increased recognition and notice of the issue. Yesterday there was a hearing, the Sub-Committee on Health has held actually three hearings in the past several months on antimicrobials resistance. April 28th was Antibiotic Resistance and the Threat to Public Health. June 9th was on Promoting the Development of Antibiotics and Ensuring Judicious Use in Humans. And then some animal health questions came up during that hearing. And they scheduled one yesterday where actually we have a lot of members that are here today, in our audience, that actually testified yesterday.

So, I’m sure if you have time and you want to talk to them they can probably tell how the hearing went. But that was titled Antibiotic Resistance and the Use of Antibiotic in Animal Agriculture. And from what I understand was a very long, long hearing over four hours, or pretty close to it. At 2:00 yesterday, I think Rich was saying, getting over at 6:00 p.m. So a very long issue. So, again, increased recognition and notice.

(Slide)

And our strategy at CVM is a multi-pronged strategy. It’s including expanded research activities, a revised safety assessment process which is Guidance for Industry 152. It’s not revised anymore. It’s been in action for about seven years. Increasing our education, out-reach activities, international collaboration, via working with WHO, Codex and OIE and as well as why we’re here today, enhance surveillance activities via the NARMS program.

(Slide)

These are our research programs. This is, they’re located in the Division of Animal and Food Microbiology within the Office or Research. And that up until two months ago Doctor McDermott lead that division as well. And for those of you who don’t know, Doctor McDermott is now the Deputy Director of the Office of Research. And we’re actually trying to hire a new Director of the Division of Animal and Food Microbiology. So if you’re interested, it’s actually currently posted on USA Jobs until Friday.

So, please throw your hat in the ring if you would like. It’s a great place to work and does some very cool stuff.

So, they’re a very diverse research program. They’re looking at standardizing, validating susceptibility testing methods in conjunction with CLSI. Some of the work that came out of this group for the standardized methods for Campylobacter, measuring the effects on veterinary antimicrobials on emergence of resistance in zoonotic foodborne pathogens. Doing a lot of genomic fingerprinting, genetic methods in collaboration with USGA and CDC in looking at foodborne pathogens, and a lot of focus too on plasmid.

We’re seeing a lot of multi-drug resistance on extra chromosomes elements, in particular plasmids where some of the work we did with GA Craig Venture Institute at the University of Maryland showed one plasmid in particular had up to 17 resistance genes on the same plasmid, which is amazing, including disinfectant resistant genes and heavy metal resistant genes at the same time, raising the question of what’s the actual true selection pressure when you look at these multi-cassette plasmids.

(Slide)

So, for those of you who have been dealing with drug approvals understand this, we’ve been doing this now since 2003, this is our Guidance for Industry 152. It’s a microbial food safety risk assessment. The title is Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern.

(Slide)

It’s essentially a risk assessment approach to look at public health hazards associated with approval. And it’s a taking from hazard characterization and through a qualitative risk assessment which includes a release assessment piece, an exposure, a consequence. They’ll get combined into a risk estimation which then turns us into our possible mitigation steps.

And we feel that this has been very successful for us and also with the drug industry in putting out their set of information of how to pursue drug approval on some antibiotics that may have a public health concern because of their overlap of use in human medicine.

(Slide)

It is a work in progress. It’s not the end of our work. Again, it’s tied in with a lot of the research going on and the literature. We need to look at, continue in areas of cross-resistance and linked resistance, that’s not really taking into that much account in this document. And also transfer resistance determinants.

But we’re always constantly seeking input. We want to rely on science and evolve the risk management paradigm.

One of the major things we’ve been looking at is Appendix A in our guidance, is a listing of antimicrobials and their importance to human health. And they are broken down by critically important, highly important and important. And that that list was designed over seven years ago. So we think it’s time to take a look again at this list with input from our stakeholders and we plan to be doing that over the next year or so.

(Slide)

This is what’s getting a lot of attention. This was released, I think, a week ago or two weeks ago. Our Guidance 209, Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals. It was released June 28th. And it was to inform the public of FDAs current thinking on the use of medical important antimicrobial drugs in food-producing animals. And outlines several broad principles for assuring judicious use.

And the document recommends phasing in measures that would, one, limit uses in food-producing animals that are considered necessary for assuring animal health and also including increased veterinary oversight or consultation.

For those of you that would like to make comments, just to let you know, it is -- we are seeking public comment on the draft guidance through August 30th, 2010. I don’t have the web site, but see Joanne Kla, she can tell you the web site if you would like. You can submit electronic comments to the docket. And then we’ll go back and take a look at all the comments and then see what our next steps are after that.

(Slide)

International activities, as Pat mentioned we’re doing quite a bit of international activities. And they’re critical because foodborne disease and resistance are global problems. We know the rapid globalization of food production and trade has increased the potential for international incidents. And we’ve done some work with the Danes in particular that showed a transmission of a ciproflox and resistant S. Swartzengrund from Thailand that infected travelers from Denmark that went back to Denmark. And then also was found on imported chilies from Thailand that entered into the United States, that we found the same strain. So definitely shows examples of global discursion of resisting clones.
And there is also a need for international harmonization to ensure data comparability. NARMS, CLSI, UCAST, some other programs internationally, we have different break points for different drugs, so it’s tough to compare data sometimes. There’s a lot of efforts ongoing to look at those datas and compare them so we can get a true understanding of what’s happening globally.

(Slide)

There’s also a new task force. In the 2009 the US and EU established a transatlantic task force on urgent antimicrobial resistance issues. And it’s focusing primarily on human use, antimicrobial therapeutic use of antimicrobial drugs in the medical and veterinary communities, even though that says that, it’s really focusing on human use. Because you know they’re looking at a lot of the major problems in healthcare and community associated drug-resistant infections and in particular strategies to improve the pipeline.

As you know, if you’ve been at ICID this week you’ve heard many speakers talk about the pipeline as almost completely run dry. There is just not profit anymore for pharmaceutical industry to go after an antibiotic that has a very short time of being used. They’d rather put their money into something that you’re going to take for a long time, like a Lipitor or something else. A chronic drug, right. They’re going to make a lot more money on.

And then also too, -- FDA has made it sometimes a little difficult to get new antimicrobial drugs approved based on the inferiority studies that they make industry do. But we’re working on that.

(Slide)

I won’t talk too much about AGISAR, because I believe I will talking about this, but this is a new body under WHO guidance, the advisory group on integrated surveillance and resistance. And this is to bring together a lot of surveillance programs globally to talk and -- to look at, as Pat said, to enhance communication, share lessons learned, where they need to go and it is to exchange information expertise, in all matters relating to antimicrobial resistance surveillance programs.

The most recent meeting was up in Guelph on June 10th, and I know from at least an NARMS program that Pat and Paula attended. So, I believe it was a well attended meeting. And that -- I don’t know when the next one is but hopefully we’ll hear more from Paula when she talks.

(Slide)

OIE, we’ve worked with OIE in the past in helping them with some of their guidelines and their terrestrial animal health code. This came out of an OIE ad hoc resistance working group that was probably eight years ago. And it was four particular areas, harmonization of national antimicrobial surveillance and monitoring programs, Chapter 6.9 is monitoring the quantities of antimicrobials used in animal husbandry, Chapter 6.10, responsible and prudent use of antimicrobial agents, and 6.11, risk assessment for antimicrobial resistance arising from use of antimicrobial in animals.

And our guidance on 152 is based on this Chapter 6.11. Now, we heard the OIE may be trying to reconstitute the OIE ad hoc group, and revisit these. I think it’s a good time. They’ve been, you know, they were developed, like I said, eight years ago, it’s time to probably update them like everything else we’ve been doing.

(Slide)

The last one that we had quite a bit of involvement was actually -- it’s now published in the "Manual of Diagnostic Tests and Vaccines for Terrestrial Animals," and the chapter is Laboratory Methodologies for Bacterial Antimicrobial Susceptibility Testing. And this provides guidelines and standards for AST methods for OIE member countries that may not have much contact say for example with Clinical Laboratory Standards Institute in the United States. It’s based a lot on what CLSI does but it provides kind of the outline of what a -- say if a government is going to start up testing the look at resistance, what they need to follow in terms of validating their susceptibility testing methods, how to interpret it, how to report it and so forth. And that’s being revised now for the next manual. It’s going to be out for comment hopefully in the next couple of months.

(Slide)

The Codes Ad Hoc Task Force. This is one that we’ve been involved now since 2007. And the basis behind this is to develop science based guidance, taking full account of its risk analysis principles and the work and standards of other relevant international organizations, such as FAO, WHO and OIE.

The objective is to assess the risk to human health associated with the presence in food and feed including aquiculture -- it’s very long as you -- when you get into Codex you end up throwing in a million words to make sure everybody is satisfied. Through food and feed of AMR microorganisms and AMR genes and develop appropriate risk management strategies. There’s a lot in there. But we’ve been doing that for four years.

(Slide)

And we had our third session October of 2009 in the island of Jeju, is a beautiful place. It’s very difficult to get to. But we had 148 delegates from 43 member countries attend. One member organization and observers from eight international organizations.

The United States lead the e-working group that came up with the proposed draft guidelines for risk analysis of foodborne resistance. We made significant progress and advancing the document that -- these are long meetings, these are like five days meetings where you work and work and work. So, even though you’re in a lovely place called Jeju, you don’t get to see too much of it until very late at night, because you seriously are working every minute to come up with this document.

(Slide)

So, we have a large delegation. It’s a nice delegation made up of consumer groups, industry, as well as government and interested individuals from academia. A lot of these folks are actually here in this room. And I -- again, my thanks to them for participating in the Codex process.

(Slide)

We do have one more meeting. It is our last meeting. We had a finite time line given to us by Codex, four years. So the first session is going to held in October in Muju, which looks like a beautiful area in the mountains of South Korea. And the net result will be a Codex antimicrobial resistance risk analysis approach that allows countries or regions to implement actions based upon identified and prioritized needs and resources.

So, if you would like to be involved in the Codex please let us know because we can add you to our e-mail list. We do that quite a bit. Merton Smith is our coordinator of that. And he’s very easy to reach on the e-mail, any FDA e-mail is usually your first name dot last name at FDA dot HHS dot gov.

(Slide)

Lastly, our public health action plan to combat resistance, this has been going now also for 11 years. And it’s a blueprint for specified coordinated federal action to address the emerging threat of resistance. It’s been broken down into four areas, surveillance, prevention and control, product development and research. And it’s currently being revised and we have seen a final revision. It is going through HHS clearance right now.

And what we’ve done is we had it written and then we had a new administration come and they took a look at it and they said we don’t see any metrics in this. And it was just kind of a reporting. So the three co-chairs, NIH, CDC and FDA got together and said, you know, we need to throw in some metrics with some time lines so we can check off objectives to be met.

So, we redid that very quickly this year and now it’s in HHS clearance, and hopefully once it gets approved through HHS it will be put out into the public and we’re hoping that will happen shortly.

(Slide)

And then lastly, NARMS, I don’t have to say too much. This is why we’re here today and tomorrow. So, it’s a very good program. It’s one of the better programs where we can say where we have a unified approach through USDA, CDC and FDA. A lot of people promote this collaboration and it’s worked well, and I hope it will get better every chance we can.

(Slide)

So, lastly, summary, obviously resistance is a complex issue. We’re always constantly gathering data. It is a global concern, just not a domestic concern, it is global and I’m glad we have so many international partners here attending this meeting.

And FDA is trying to develop a realistic approach with coordinated federal activity, through increased research, taking that research and translating it into regulatory policy, better surveillance and increased outreached, as well as education to our stakeholders.

(Slide)

And with that, thank you very much.

(Applause)

DR. McDERMOTT: I think what we can do if you would like, I mean we set aside question and answer sort of for the end of the morning session, but if you would like and if there are questions while we’re changing between speakers, that’s fine. Please go right ahead.
Okay. Thank you, David. Our next speaker from CDC, Doctor Rob Tauxe. I think everyone in this room knows Rob. He’s Deputy Director of the Division of Foodborne, Waterborne and Environmental Diseases, part of CDC’s National Center for Emerging Zoonotic Infectious Diseases, unless I’ve got the old one and not the new one, which I can barely keep pace with. Sorry, Rob.

His interests are the epidemiology and pathogenesis of infectious diseases, antimicrobial use and resistance and Doctor Tauxe will give us the overview of activities at CDC.