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U.S. Department of Health and Human Services

Animal & Veterinary

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Antibiotic Breakpoints: Methods for Determining and Use by Medical Community

Dr. Al Sheldon

DR. SHELDON: I will tell you that I have an autograph of Wayne Gretzky, great guy, and it is for sale.


There we go. Good morning, ladies and gentlemen, distinguished guests, colleagues from the Center for Veterinary Medicine. It is clearly a pleasure to be here today to discuss with you the establishment of interpretative criteria, i.e. breakpoints for use in human medicine.


Now, before I do, I would like to discuss the regulatory process that is involved in setting up the breakpoints. The establishment of breakpoints really is a multi-step process that occurs in two different stages.

The first of these occurs during the investigational new drug stage which is the stage where the company is investigating the utility, the potential clinical utility of the drug in clinical settings. Therefore, the Agency requires that the company submit experimental preclinical data to help establish the provisional breakpoints that are going to be used in Phase 2 and Phase 3 clinical trials.

As my presentation proceeds, I will go into greater detail about the specifics regarding the requirements that need to be submitted during the investigational new drug stage.

Now, the second stage is really once the sponsor has completed all of the investigational data and they have done the analysis and they feel that the produce now can be submitted to the Agency for evaluation and approval. This is done through the new drug application stage.

In this particular instance, the Agency requires the submission of clinical data to allow evaluation of the correlation of the provisional breakpoints with the clinical outcomes that have been derived during the clinical trials.


Now, this is -- this slide provides information that is very important. And it is important because it describes the methods that are used and what is required of these methods in doing these kinds of studies. We have to have confidence in the data generated during produce development. That is, it is essential that the susceptibility test method be standardized, reproducible in order to assure precise and accurate results that have been derived during the clinical trials.

It is important in doing any surveillance studies that you have accurate and reproducible methods in order to have confidence in the data that you are evaluating. Therefore, the FDA requires the use of susceptibility test methods established by standard-setting organizations. We use the methods that are established by the National Committee for Clinical Laboratory Standards.

We also determine whether a correlation exists between the MIC and dish diffusion methods that are used by sponsors. We need to understand that if an organism is considered susceptible by an MIC method, it is also considered susceptible by a dish diffusion method, i.e. for resistance.

We also establish quality control ranges. At this point, I would like to describe the fact that not only -- the FDA sets breakpoints. These breakpoints, the quality controls and a listing of this information is included in the package insert that is approved with every NDA. There is also an independent organization, the National Committee for Clinical Laboratory Standards, that also establishes breakpoints.

So we want to make sure that we are not sending mixed messages to our constituents, i.e. the users of these drug products. So the NCCLS actually has invited me to become a member of the Antibody Susceptibility Testing Committee to provide our views on the breakpoints that we have established to try to assure that we are -- that we have the same kinds of breakpoints and that we are not sending confused messages to our constituents.


Now I would like to discuss the kinds of microbiological studies that are submitted during the investigational new drug stage. The preclinical information required to aid in establishment under the provisional breakpoints is as follows: We require studies on the mechanisms of action. We need to understand the physiological and the morphological effects of the drug.

And, therefore, we need characterization of the targets the drug is likely to be affecting. This includes things like DNA replication, transcription, translation, biochemical pathways because this provides us an understanding of how resistance might emerge by changes in target side.

Now, clearly we know that there are other mechanisms of resistance which are important. And I will discuss those at a later time. We need to have a clear understanding of the antimicrobial spectrum of a compound. This activity that is the spectrum helps us characterize the potential clinical utility of the antimicrobial under investigation.

The susceptibility profiles are presented usually as histograms and population distributions. And these kinds of data help us assess where the breakpoints might be considered.

Now, as I tell you about the kinds of things that need to be submitted, you must understand that it is a compilation of all of these thoughts and all of this data and all of this information that goes into making or describing what would be the most appropriate breakpoint.


Now, the mechanisms of resistance also aid in the establishment of the resistant breakpoint. Resistance mechanisms can limit the effectiveness of antimicrobials in clinical settings. Thus, we require characterization of their mechanisms and their distributions within targeted clinical populations.

The relationship of the increased susceptibility of these pathogens to the pharmacokinetics and pharmacodynamic parameters of the drug are assessed to determine probable breakpoints. Cross-resistance to drugs of either the same class or different classes mediated by different kinds of resistance mechanisms must be provided, again, to provide insights on the potential utility of the drug.


Animal model studies are also very important during product development. They are used to assess the potential efficacy of the drug in either prophylactic models or in therapeutic models. They are used to investigate the nature of the disease process and how the product works against the specific diseases that are investigated.

They are also used the characterize the pharmacokinetics of the antimicrobial and to make decisions about the kinds of doses that should be used in humans. They also -- the efficacy aids in characterizing relevant pharmacodynamic parameters, also. These observations, again, provide additional evidence used in setting of the breakpoints.


Now, pharmacokinetics and pharmacodynamic studies have been elevated to a greater degree of science in that we must have a good understanding of the absorption, distribution and metabolism and elimination of the antimicrobial, the serum protein binding which may affect the utility of the drug, and tissue distributions.

The tissue distributions are important because they allow us to assess whether sufficient drug is present at the site in relationship to the MIC of the organism that is being treated. This information and the animal model studies help us examine the relationship between the efficacy and the pharmacokinetic and pharmacodynamic parameters. These operations, again, provide additional evidence that is used in setting the breakpoint.


Now, an example of pharmacodynamic parameters that are emerging from animals and limited human clinical studies are as follows: time above the MIC for beta lactim antimicrobials, it seems to be a pharmacodynamic parameter that is important. That is, the time the drug concentration remains above the MIC should be greater than 80 percent of the dosing interval to achieve successful clinical outcome.

For fluoroquinolones, the AUC to MIC ratio is important. If this value is greater than 30 for gram positive bacteria, for example, we have a higher success rate in terms of clinical efficacy or lower mortality.


In summary, it is a compilation of data derived from different, but very related different types of studies which are used to provide insights into the activity of a drug and its clinical efficacy. This information is used to set the provisional breakpoints that is used in Phase 2 and Phase 3 clinical trials.


Now I would like to talk about the information that is required for the new drug application. And basically what we want to establish is a correlation between the breakpoints that have been established and the provisional breakpoints that have been established during the investigational new drug stages and their ability to predict what happened in the clinical trials during Phase 2 and Phase 3.

So we are trying to establish a correlation between MIC results and clinical outcome. And that includes both bacteriological and clinical outcome. And this has an important aspect of the evaluation process because it validates what we have set provisionally as the appropriate breakpoints.

Now, the down side of this approach is that in essence we are only validating the susceptibility breakpoint because we only allow for inclusion in the evaluation of efficacy of a product organisms that are considered susceptible by the provisional breakpoint.

We really don't validate the resistance breakpoint. We rely on resistance mechanisms that are available to try to determine where that resistance would occur.


Now, what is the purpose of susceptibility testing? I will have to leave you with these thoughts. Is susceptibility testing performed to predict clinical utility and outcome or is susceptibility testing performed to monitor changing susceptibility patterns in the emergence or resistance, or is it both?

The approach that you take -- or the philosophical approach that you take can influence the breakpoint that you establish. The debate certainly will not be settled in the near future because I can remember from microbiology back in my old days that this kind of question was continuously being asked. That concludes my presentation. Are there any questions?


DR. BEAULIEU: Thanks, Al. Our next speaker is Dr. Tom Shryock. Dr. Shryock has an advance degree from my alma mater, Ohio State University, which is unchallenged in its academic excellence, at least by anyone I am willing to listen to.


However, they have fallen on hard times on the football field lately and we won't go there. Dr. Shryock also has two post-docs in cystic fibrosis and pulmonary infections. He is currently the technical advisor in microbiology for Elanco Animal Health.

He has previously had experience in research and development of animal drugs at Pfizer Animal Health and he was an Assistant Professor at Indiana State University. He is also currently a chair-holder I think at -- on the NCCLS. And he is here this morning to talk to us about antibiotic breakpoints, methods for determining those and their use in the veterinary medical community.

Does anyone in the audience happen to have a laser pointer or know where there is one in the room? Thanks.