Veterinary medicine advisory committee

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The Importance of Antimicrobial Drugs for Human Medicine

DR. GOLDBERGER: Thank you.


Just by way of introduction, I am Director of the Division of Special Pathogens within the Center for Drug Evaluation and Research, and we have the responsibility for a substantial number of anti infective products, including the fluoroquinolones, drugs for anti parasitic disease, drugs for systemic antifungal disease, drugs for microbacterial disease, and some assorted other products. It is a pleasure, obviously, to be here today.


This exercise of looking at the importance of antimicrobial drugs for human medicine was taken at the request of the Center for Veterinary Medicine. I should point out that under current CBER regulations a product must be safe and effective in order to be approved, however, demonstrating a specific level of importance in human medicine is not required.


However, many of our regulatory initiatives recognize that some products may be of greater importance in human medicine, and subparts E and H, which I will talk about in slightly more detail in a couple of minutes, deal, for instance, with serious and life threatening disease, as well as the recently approved FDA Modernization Act which includes what is called the "fast track" designation for certain products.

For those individuals who are interested in a more detailed discussion of issues related, for instance, to definitions of serious and life threatening diseases, one useful resource is the Federal Register, and the citation is 52:19466 19477, May 22, 1987. This was a section that dealt with the IND regulations, and there is a substantial discussion of the topic of serious and life threatening disease.


Let me also say that our approach was constructed without regard to risks that veterinary use might or might not hold. It is intended to represent the importance of antimicrobials in human medicine. Obviously, our approach is then to be placed in a larger document.

After discussion with the Center for Veterinary Medicine, we did include specific language regarding treatment of foodborne infections. However, I did want to say that we do not regard the issue of importance of the antimicrobial drugs by any means to be limited to that type of infection.


We put together our approach by utilizing some of the resources within the Center. A number of medical officers from my Division and the Division of Anti Infective Drug Products as well as microbiologists from those two divisions met weekly for a period of several months. After we put together an approach we had it reviewed internally, a little bit within our Center at the level of the Office of the Commissioner, including the new coordinator of antimicrobial resistance activities for the agency, Dr. Jesse Goodman. Then externally, we shared our approach with our colleagues at the Center for Disease Control.


I did want to make, however, some caveats and a comment about this. First of all, and I think that this will come as no surprise, the importance of a product in human medicine will sometimes change over time and whatever approach is going to be used will need to recognize that.

Our system is currently qualitative rather than quantitative. I think that this is an issue that may need to be revisited over time, depending on the construction of the ultimate approach to these issues.

There is a component of subjectivity in determinations of the importance of drugs in human medicine. I had originally thought about titling this "there is an unavoidable component of subjectivity" because that, in fact, reflects some of the issues with medical practice.

Finally, we expect and invite comments. We do not regard this as a completed work. I mean, this is now being presented publicly as part of the larger framework document and we would expect that there will be some modifications over time that will need to be made, as well as discussion at different points on how the actual implementation of this approach will need to be done.


In doing this, we tried to look at several different categories. That is, the disease, drug or drug class, and the availability of alternative therapy.


Well, as far as the disease, we were thinking primarily in terms, not surprisingly, of severe or life threatening disease. Again, as I indicated earlier, these definitions have been previously recognized in existing regulatory initiatives. In particular, the subpart E regulations dealing with serious and life threatening infections, 21 CFR 312.80 and our accelerated approval regulations for products, again, for serious and life threatening disease, 21 CFR 314.500, as well as in the recent FDA Modernization Act.

As I indicated earlier, we also included some specific language about foodborne disease. I think this is important given some of the data that exists about transfer of pathogens from animals to human beings. Nonetheless, I do want to emphasize as we think about the importance of drugs in human medicine we are not certainly, from our approach, limiting this to importance in foodborne disease.


As far as the drug or drug class, again, I think our emphasis as we thought about this was on serious diseases, drugs that were effective in serious diseases and also drugs that were active against resistant pathogens. I think that is, obviously, an important aspect of this.

There is also, I think, an interest in looking at drugs that may have a unique mechanism of action, recognizing that products like this over time may occupy a very important role in human medicine.

Finally, certainly we looked at issues related to mechanisms of resistance and cross resistance. In terms of issues like that, let me just say a couple of things. One is that there is certainly a recognition that a product in a class may often, when it produces resistance, produce resistance to all the drugs in the class. That is by no means invariable but it tends to be more common than not, and I think that this is an important issue as we think about a product, for instance, that might have veterinary use, might not be the identical product that is used in humans, but we must recognize that if resistance develops to one product it is likely to develop to many others.

We also had some discussion about whether or not we could make definitive comments about mechanisms of resistance or resistance transfer, i.e., chromosomal versus plasmid mediated resistance. I think that this may be possible now but, as we talked about it, we could see different approaches to that and, at the moment, we believe that rating the comparative importance of any system like this is not easy. Again, this is something that may need to be revisited at a later point.


I think, therefore, a crucial issue that came up, not surprisingly again, reflecting the way physicians approach the management of patients with serious illness is the availability of alternatives in treatment. And, I think one way we thought about this was that there are essential agents, that is, these are drugs for which really currently there are no adequate substitutes or replacements. There are also drugs of choice for infections or important therapy by alternatives exist. Finally, there are drugs that realistically appear to be of lesser importance, that may no longer have major use in human medicine. There may be really little therapy of serious infections with them, or they may have basically essentially been replaced for almost all infections. We think that these categories are extremely important in looking at the overall issue.


Using the above, drugs were placed into one of three categories. Again, I think practically speaking, at present time most of our emphasis probably is in looking at issues related to serious disease and alternative therapy, however, over time issues of resistance, cross resistance and unique mechanism will probably grow in importance.

We had originally used a more quantitative approach. When we first thought about this, we thought in terms of potentially using a point system, looking at different issues about drugs resistance, etc. And, I think the advantage of this is that there is a possibility of better discrimination between products and this may turn out to be fairly important.

The drawback, however, is that there is a difficulty in determining what the appropriate points and weights for different categories ought to be. So, this is an issue that we may very well need to revisit, but we must keep in mind that although on the surface it would seem as though using a point system would provide greater discrimination, and it may, we must recognize that it also carries the potential for a lot of subjectivity and we would have to be careful how we did this.

In particular, we may need to revisit this issue ultimately because in the ranking as proposed in the framework document one can note very easily that Category II is the largest and the most heterogeneous and, depending on what types of studies, etc., are going to be needed among products in that category, it may be necessary to revisit the system and see if we could provide a little better definition.


Category I    and I have titled it "essential agents" because I think that is one of the most important aspects of it, although not the only one    are drugs really for serious and life threatening disease, essential agents where there are no substitutes, or important for treatment of foodborne infections where, due to resistance or other reasons, there are really limited alternatives, and finally, the mechanism of action or the nature of resistance induction is unique. Keep in mind that these by no means are necessarily mutually exclusive. The fluoroquinolones, for instance, which are one of the examples I have for multi drug resistant Salmonella, although they are very important in serious Gram negative infections and increasingly important for Gram positive infections both are useful in serious or life threatening disease, important for the treatment of foodborne infections and, ultimately have a mechanism of action and nature of resistance induction that are somewhat unique.

So, drugs may be in more than one category here. And, as I mentioned, examples that we have and, again, these are not meant to be comprehensive are vancomycin for methicillin resistant Staph. aureus and serious Group D strep infections, and the fluoroquinolones for multi drug resistant Salmonella.


Category II, drugs of choice, important therapy but alternatives exist. A couple of examples we thought of are ampicillin for the treatment of Listeria infections. Again, ampicillin is the clearly I think the preferred therapy, however, timethoprin sulfa is an important and useful alternative. Erythromycin for Campylobacter infections    again, at least one alterative currently are the fluoroquinolones.

We recognize here that, again, there will be a number of diseases, a number of drugs in this category, some which are stronger choices than others; some for which there will be multiple diseases, others there may be only one. So, it may be necessary over time to revisit Category II a little bit to get a little better definition.


Finally Category III, the drugs of lesser importance. Again, little or no use in human medicine, neither the first choice nor an important alternative for human infections. Examples that come up, for instance, are ionophores and polymixins, and there are certainly others as well.


As far as unresolved issues, I think clearly, as I indicated before, are issues related to refining this approach. Do we need to get better discrimination between products? How exactly in the future will we deal with new products? I think these are certainly important issues.

We need to make sure that our integration into the complete document is satisfactory so that it is clear enough and is understood by the various constituencies that will be involved.

Finally, obviously, and this goes beyond simply the CDER component, is addressing the implications of what we have here. Obviously, this is an important aspect for human medicine. It now needs to be fit into a more complete document and, in fact, we now need to understand how we are going to successfully utilize this. Thank you.

DR. STERNER: Does anybody from the panel or invited speakers have questions for Dr. Goldberger? Yes? If you will state who you are and where you are from also?

DR. SALYERS: Abigail Salyers, University of Illinois. First a comment and then a question. The comment is I don't think you should make a difference between chromosomal and plasmid location because there are integrated elements called conjugate transposons that are widely distributed, or found very often in the Gram positive bacteria and some enteric bacteria which are in the chromosome but they are very transmissible, having a broader host range than a lot of plasmids. So, I think you are right not to try to make that kind of a distinction.

Mu question is that people keep talking about antibiotics that are of importance in human medicine, and they use that in the present tense. Is any thought being given to taking into account the drugs that are coming through the pipeline at the present time that may be important in the future?

DR. GOLDBERGER: Yes, I think that one of our goals is to attempt to do this at a relatively early stage, and I think obviously we need to have some discussion about when is the most appropriate time in terms of how much information might be needed, for instance, from clinical trials to be able to begin to make such a determination.

But the basic answer to your question is, yes, we think this is important and, in fact, it is products like that which make me think that over time the category of unique mechanism of action or unique mechanisms of development of resistance may become more important as we see genuinely new classes of antimicrobial therapy.

DR. SALYERS: Not to hog the floor here, but just one more thing. There is another aspect of this that maybe should be considered also. Right now there is a large clinical trial of erythromycin treatment to see if this intervention is going to help with heart disease. If that pans out, then all of a sudden the macrolides are going to be a lot more important than they have been in the past. So, there are also new uses of antibiotics in medicine.

DR. GOLDBERGER: Well, if you recall, that was under my caveats, that the importance of antimicrobial therapy will change over time and we can think about examples of that, I mean, if you think about the role of vancomycin today and the role of vancomycin twenty years ago, as an example; if you think about the potential role of erythromycin not only in terms of Campylobacter which was the example that we used but also in terms of the role that it has had for many years, perhaps being supplanted recently in terms of the management of a typical pneumonia which became more and more of an issue starting in the later 1970's.

So, we recognize that as changes occur in medical practice, changes occur with emerging infections, there will need to be these alterations. We also need to recognize that it may be that some products that occupy a relatively important position now will be supplanted by newer drugs, either because the newer drugs are better, less toxic, or because resistance issues have rendered some products less useful than they seemed to be. But I certainly agree with you that these are issues that are important, and in the ultimate implementation of this approach will need to be taken into account.

DR. STERNER: Dr. Angulo?

DR. ANGULO: Mark, of the parameters that you list, the one that you did not list is the likelihood of genetic transfer. On page 14 of the framework document it discusses the possibility of taking the categories that you have placed and treating a Category I or II drug as a Category III drug if the likelihood of genetic transfer is deemed to be low. For instance, it points out that if a drug is an essential drug for the treatment of respiratory disease in humans and the likelihood of transfer of genetic resistance from an enteric organism in animals to the respiratory pathogen in human is thought to be low there would be this treatment of Category I or II into Category III.

My question is in your consideration of the parameters, did you consider this concept of likelihood of genetic transfer as a parameter for categorizing importance of human drugs?

DR. GOLDBERGER: Actually not. It is not that we didn't consider it. This was considered as part of the overall of the overall framework document and, as you pointed out, is included in it. Our goal was, as an initial step, to try to focus primarily on how we would prioritize drugs in their importance in human medicine based on information and issues related, I think, to medical practice, the products themselves.

Subsequently, as this approach is integrated into the entire framework document, alterations in categorization, etc., may be made based upon other data. But our first goal was simply to get some sort of approach to how we thought of the drugs themselves. Whether drugs get moved up or down by other factors is an issue that I think needs to be addressed in the totality of the document rather than just in our approach.

But, certainly, this is an important issue and I think it is an important issue in terms of the concept, and it is an important issue in terms of how we would actually go about demonstrating that aspect about the level of transmission, and I think that is going to be one of the more challenging aspects to this whole exercise.

DR. STERNER: Thank you, Dr. Goldberger. The next speaker is Dr. Peggy Miller, from the Center for Veterinary Medicine, explaining the animal drug approval process for antimicrobial agents.

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