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U.S. Department of Health and Human Services

Animal & Veterinary

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Evaluating Risk from Resistant Pathogens under FFDCA

Linda Tollefson, D.V.M.

DR. TOLLEFSON: We are moving from jois de vie to Food, Drug and Cosmetic Act. And I think there is quite a bit of difference between those two. You can't time me now until I get this.

DR. STERNER: It's coming now, Linda.

DR. TOLLEFSON: It's okay.


This afternoon after lunch, we have asked several experts to discuss in a panel format how FDA should evaluate the human health risk attributable to resistant pathogens. And as Dr. Hueston pointed out, this is a very difficult topic because it does encompass both science and public policy.

Now, the purpose of my presentation, what I would like to do is lay out what FDA is thinking on this issue as we develop what is now generally referred to as the Framework Document and then more recently, our analysis of the comments on the Framework Document. And the analysis of the comments is available out at the registration desk if you haven't gotten that yet.


FDA operates under the Food, Drug and Cosmetic Act and the regulations adopted under it. You heard a lot about it this morning. Section 512 is one of the safety standards that establishes conditions of approval for new animal drugs. And in that section, it requires that the drugs be proven to be safe.

Now, prior to the addition of this section to the Act by the Animal Drug Amendments of 1968, animal drugs were regulated under several sections of the Act. And Dr. Rulis mentioned the Section 409 which is the food additive provisions. Substances formed in or on food due to the use of animal drugs were regulated under the food additive provisions in this Section 409.

Dr. Rulis also pointed out that neither Section 512 nor 409 provides a definition of safe. However, the legislative history of Section 409, the food additive amendments -- again, Dr. Rulis covered this briefly -- states that safety requires proof of a reasonable certainty that no harm will result from the proposed used of the additive. Okay


A similar definition of safety in the context of food additives has been established by regulation. And that statement is very similar. It states that there is a -- safety means that there is a reasonable safety in the minds of competent scientists that the substance is not harmful under the intended conventions of use.

The regulation goes further and states, as the legislative history does also, that this does not mean that we can establish with complete certainly the absolute harmlessness of the use of any substance. Also, that safety may be determined by scientific procedures or by general recognition of safety in some instances.

And in determining safety, the follow factors shall be considered: the probable consumption of the substance and of any substance formed in or on food because of its use, the cumulative effect of the substance in the diet, considering any chemically or pharmacologically-related substance or substances in that diet, and then safety factors which in the opinion of experts who are qualified to assess this are generally recognized as appropriate. So that it is a whole paradigm rather than a strict definition of safety.

Now, the Agency has consistently applied the reasonable certainty of no harm standard in determining the safety of substances formed in or on food as the result of the use of an animal drug. Dr. Kevin Greenlees earlier this morning provided an overview of how the Agency applies that standard to animal drug residues.

It is clear, however, that there is a significant difference between the traditional residue-based determination of the safety of animal drugs intended for food animal use and the determination of safety in the context of antimicrobial resistance of resistant pathogens.


The former involves the risk of consumption of the chemical substance formed in or on the food as the residues of the drug. This risk is not anticipated that it will change appreciably over time. Safety in the context of antimicrobial resistance involves assessment of the risk of a substance, in this case resistant microbes, which may increase in prevalence over time as a result of the use of the drug in animals.

Now, FDA recognized the difficulties associated with managing this nontraditional risk. We have been attempting to do this now for a few years. And we outlined a mechanism to deal with it. Late last year, the Guidance for Industry and the Framework Document.

In November of 1998, FDA issued guidance for industry that stated the regulatory system for assessing the safety of antimicrobial drugs intended for use in food-producing animals should be modified to address microbial safety concerns, in addition to the toxicological safety concerns that we had always addressed. We emphasize that this included all uses of all classes of antimicrobial and new animal drugs for use in food-producing animals.


Then in December of 1998, we issued a discussion document which laid out a conceptual risk-based framework for evaluating microbial safety of antimicrobials intended for food animals. Implicit in the Framework Document is the application of the safety standard in a manner that ensures protection of public health by preserving the effectiveness of antimicrobial drugs for treating diseases of humans, that is by assuring that the ability to treat significant microbial diseases of humans is not lost.

Now, in developing this Framework Document, we did recognize that having a resistant infection in and of itself may affect human health, even when alternative antimicrobial therapies are available. And it may be appropriate to initiate mitigation efforts on the basis of those effects.


However, in order to permit the graded level of regulatory response to the development of resistance that was outlined or proposed in the Framework Document, we viewed harm associated with the use of an antimicrobial drug in food-producing animals as loss of the long-term availability of safe and effective antimicrobial drugs to treat human disease.

We were pretty explicit about that. Also, I thought it was interesting this morning that EPA developed a similar definition of harm in their review of the gentamicin for pesticide use.

Now, inherent in this definition is an assessment of alternative therapies available to treat a particular disease, alternative therapies to humans. What we did was make an for assessment of microbial risk through an initial categorization process which considers the importance of various drugs or drug classes to the treatment of microbial disease in humans.

FDA felt that it was crucial to first determine the drug's importance to humans before determining what effect the development of resistance to that drug from animal use will have in human health. We fully intend to expend most of our regulation oversight then on the drugs of most importance to human health.


FDA proposed three categories based on importance of the produce in human medical therapy. Drugs in Category 1 represent those of highest public health concern. And that is the only category I am going to mention this morning.

For these drugs, FDA believes that human exposure to resistant bacteria from animals must be avoided or extensively minimized to assure that these drugs remain effective for human medical therapy.

Drugs would be placed in Category 1 if they meet any of the following criteria: if they are essential for treatment of a serious or life-threatening disease in humans for which there is no satisfactory alternative therapy, or important for the treatment of food-borne disease in humans where resistance to alternative antimicrobial drugs may limit the therapeutic options, or members of a class of drugs for which the mechanism of action or the nature of resistance induction is unique.

Resistance to the drug is rare among the human pathogens and the drug holds potential for long-term therapy in human medicine.

Now, the Agency anticipated that drugs in this class, in this Category 1 class, could be used for food-producing animals if controls could be put in place to ensure little or no resistance transfer from the treated animals to humans with respect to the human diseases of concern.

And we actually went a bit further and provided specific examples in the Framework Document to further illustrate our thinking on the categorization of drugs. For the quinolones, we considered that was very important for serious infections caused by multi-drug resistant Salmonella species where it is resistant to Category 2 drugs or perhaps another Category 1 drug.

At this point in time, we still are not certain which drugs are going to be in which category. That is still open for public comment and further work.

Quinolones are frequently the primary treatment for Salmonellosis. And quinolones are also the drugs of choice in alternative therapies for many life-threatening resistant gram negative infections.

For vancomycin, we considered serious infections caused by methicillin-resistant Staph. aureus and ampicillin-resistant enterococci. Vancomycin is really the only well proven treatment available to treat serious infections with these organisms.

Now, there is quinupristin, dalfopristin or vancomycin-resistant enterococci. The human drug, Sinersid, was just recently approved for this use. And Sinersid also has the unique mechanism of action. So it meets more than one criteria. Many of these drugs do meet more than one criteria. And then third generation cephalosporins for food-borne infections, for example, ceftriaxone for Salmonella infections in children.


We received several comments questioning what safety standard is relevant to the evaluation of risk from the resistant microorganisms and we hope to receive additional input on the issue via the expert panel discussion and also the public comment period this afternoon.

What I have described is our effort to evaluate risks from the recent pathogens under the Food, Drug, and Cosmetic Act. And we have been struggling with this issue for a while. Later in the afternoon, Dr. Thompson will discuss more how to implement this through the development of thresholds or other means. But we definitely appreciate any help that the panel or others could give us.


DR. STERNER: I think one more round of applause for all of our speakers for getting us done ahead of time is called for.


DR. STERNER: Questions for Dr. Tollefson Yes

DR. CONDON: Linda, this is Robert Condon.

DR. TOLLEFSON: Yes, I know.

DR. CONDON: Well, I don't know whether you need it for the record or not. Unless they have changed in the last couple of years, in case somebody wants to go back and look at the legislative history, are not antibiotics in CVM regulated under 512


DR. CONDON: Rather than 409

DR. TOLLEFSON: Yes, that's what I said.

DR. CONDON: And the standards are a little bit different. And I think one of the main things is that those 512 are safe by all reasonable tests that are applicable.

DR. TOLLEFSON: Right, that's fine. I mean, there is really no definition of safety. Safety is under the legislative history and the 409 regulations.

DR. STERNER: Other questions for Dr. Tollefson Well, you are going to get yourself an extended noon hour. We will begin promptly at 1:00. Thank you for your attention this morning.

(Whereupon, a luncheon recess was taken.)