BreakOut Session Addendum to the October 2008 Antimicrobial ...

Break­Out Session Addendum to
the October 2008 Antimicrobial Workshop
AAVPT and the United States Pharmacopeia (USP) co­sponsored a workshop (October
23­24, 2008) to explore approaches for developing companion animal antimicrobials. The
purpose of the workshop was to address the shortage of approved antimicrobials for the
range of infectious diseases commonly treated in small animal practice.
As part of this two­day workshop, there were break­out discussion sessions aimed at
identifying alternative approaches to support approval of new animal drugs and to expand
the indications of existing drugs to meet the therapeutic needs of dogs and cats. To
promote active discussions during these break­out sessions, specific scenarios were used
to facilitate participation. A summary of the break­out session discussions are provided
below. This summary provides many individual suggestions, over­arching ideas, and
potential obstacles. The workshop was not aimed at reaching consensus on any specific
ideas or disease condition scenarios offered during these discussions but to provide a
forum for compiling possible innovative solutions to current drug development hurdles.
Additionally, innovative study designs to aid the development and approval of
antimicrobials for use in companion animals were discussed. The reader is referred to the
White Paper: Exploring Ways to Improve the Development of New Antimicrobials to
Provide Unmet Therapeutic Needs of Dogs and Cats (JVPT ADD Publish date once
available) for a full overview of the antimicrobial workshop.
Break­Out Session Summary
The organizers of the workshop ensured that each break­out group included a balanced
group of attendees representing veterinary practitioners, the pharmaceutical industry,
regulatory agencies and academia. Four thought­provoking questions were provided to
the break­out groups to facilitate discussion. The questions appear below in italics
followed by a summary of the suggestions/discussion points from all the break­out
groups.
I. What kind of scientific evidence could be used to support a new indication or
additional indications? How do the alternative sources of evidence provide
scientifically and statistically sound confirmation of effectiveness?
What information is needed to give scientific evidence (how large a sample size is
needed; what power requirements are needed) to facilitate an additional
indication or a completely new indication/drug entity?
What would you be comfortable accepting to support a new indication and
additional indications?
This question was addressed from two different perspectives: first, if the sponsor is
seeking approval for a new drug entity and indication(s); second, if the sponsor is
pursuing the additional indications for an already approved drug.

I.a. A new drug and the first indication
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If a new drug entity was being developed for a first indication, then the possibility of
including additional information (information from sources other than the field study
information) in the labeling and the Freedom of Information (FOI) summaries was
discussed. Such information is often generated during drug development. It was noted
that there are legal implications when including “additional” information in labeling and
the FOI summary, and the advertising and promotional aspects of this recommendation
would need to be investigated further. The purpose of this additional information would
be to guide the practitioner’s therapeutic decisions for the safe and effective use of the
product beyond the approved labeled indications.
I.b. Additional indication
If a drug was already approved for an original indication (field safety and margin of
safety thus already established), suggestions for obtaining an additional (supplemental)
indication included the use of a limited dataset (smaller study size with fewer animals), or
supported through one or more of the following types of data:
• A laboratory study – where a clear difference between the treated and control group
could be established.
• A single­site clinical study – such as using a shelter with a population of infected
animals.
• A combination of a laboratory study and small field study. For example, if a sponsor
wanted to pursue an URTI (upper respiratory tract infections) and a LRTI (lower
respiratory tract infections) indication for a new animal drug, it was suggested that a
sponsor might complete a full scale URTI field study (to support statistical
significance and provide inferential value). In addition, for the LRTI, the sponsor
might propose a small laboratory study to assess LRTI in the target species, provide
PK/PD information pertaining to this additional indication and propose a smaller field
study for confirming the drug effectiveness for LRTI.
• Conduct two different lab studies – utilizing diagnostic techniques not readily
obtained in field studies (e.g., BAL, and epithelial lining fluid (ELF) drug
concentrations)
• Use of validated and reproducible animal models of disease. The pros and cons of
using this approach versus a target animal model were discussed.
• Use of literature to support the additional indication. Much discussion focused on the
use of the USP monographs as a source of objective evidence­based information.
There were recommendations for study designs to expand the scope of labeled
indications. One approach was to combine multiple indications in one field study, such
as upper and lower respiratory cases or superficial and deep pyoderma cases. However,
in case of combining multiple indications, many participants believed that that would be
possible only for clinically and pathologically related claims. Another approach
suggested was to establish a relationship between drug concentrations in the blood and in

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the ELF in a laboratory study. For upper respiratory infections, evaluation of clinical
parameters during treatment and relapse period, as well as methods for assessing
reduction in pathogen counts pre and post­treatment, were proposed. Pathogen reduction
could be assessed in a laboratory study or in a subgroup of the patient population in the
clinical study. Recommendations were made for inclusion of an active control, historical
control, or negative control group with rescue. Participants expressed concern about
using a negative control for LRTI (pneumonia) in a field study or requiring cultures as
part of the entrance criteria for LRTI. One proposal was to do a laboratory study with a
negative control, to show a clear difference in the disease outcome with the treatment and
control group, followed by a smaller clinical study using an active control.
For example:
Both lower and upper respiratory disease could be incorporated into one study. Half the
cases would be URTI and half would have LRTI. In this scenario, cases having both
URTI and LRTI would be excluded. All cases would need to be evaluated at the end of
the treatment period of the study and for a defined post­treatment period to assess
possible relapse. A “successful” case would be one that was considered a “success” at
both time points. Suggestions for evaluating effectiveness of an URTI included the use of
CT or MRI of sinuses in a small laboratory study as a means to objectively assess drug
effectiveness prior to the clinical field study.
For hemoparasites, the development of reliable disease models or the use of historical
controls were discussed. The indication would likely be control, rather than treatment,
and the majority believed that experts should be consulted regarding the appropriate
endpoints to measure in a hemoparasite effectiveness study.
II. When defining an indication, what infections can be lumped together?
Considering the drug, microbe, PK information, pharmacodynamic information
for the specific drug/pathogen combination, and target site, for what other
indications could we use the drug?
Considering the drug, ‘bug’, PK information and target site – for what other
indications could we use the drug?
The specific case example described a fluoroquinolone already approved to treat
wounds and abscesses in dogs. The sponsor would now like to obtain an
indication for the treatment of UTI in dogs, perhaps including both upper and
lower UTI.
Again, the question was addressed from two different perspectives: first, as described in
the case example, the sponsor is seeking approval for an additional indication for a drug
already approved in a species for a different indication; second, a sponsor would like to
have a concurrent approval of an original NADA for two different indications.

II.a. Additional indication
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In general, most break­out groups indicated that a smaller field study might support an
additional indication than the larger field studies usually required for an original
approval, but additional supporting data would also be needed.
In the specific example given (adding an additional indication for the treatment of urinary
tract infections to an approved new animal drug for the treatment of wounds and
abscesses), a smaller study (e.g., 20 dogs) was suggested, but only if the dose is the same
for both indications. The rationale is that the larger sample numbers required for the
original approval provide substantial evidence of effectiveness and field safety in the
target population under clinical conditions of use.
If a higher dose is needed for the additional indication, then additional safety data would
be required. Supporting documentation might include urinary PK and MIC data for
common urinary pathogens not currently on the approved label.
Several break­out groups also discussed the use of historical and negative controls as a
way to decrease the numbers of animals needed in the field study. Some attendees
suggested that there be a way to utilize credible experts for specific diseases, utilizing
their expert information on extra­label drug use, and for recruiting cases for the pre­
approval studies.
Some attendees cautioned that the “down­sized” approach to field studies might not be
applicable for every additional indication. For example, while most canine UTIs are
generally uncomplicated bacterial infections, feline UTI are often multi­factorial.
Therefore, while a smaller field study might be appropriate for dogs, it may not be
suitable for adding feline UTI to labeling.
II.b. Multiple initial indications
Many participants generally believed that an original study could be designed to support
indications for the treatment of infection in different locations within one organ system.
For example, a field study might include a significant number of uncomplicated UTI
cases, but additionally, cases that have infections in several different locations within the
urinary system (e.g., complicated cystitis, prostatitis, pyelonephritis, etc.) could also be
included.
One concern with this approach is that if effectiveness in one location is not clearly
demonstrated, the lower number of cases would not support approval for the other
locations within the system. This concern could be mitigated in several ways, such as
increasing the total number of cases enrolled in the study. Alternatively, the statistical
requirements for determining product effectiveness might be changed for uncommon
diseases, for example, a significance level of p< 0.1 instead of p< 0.05.

II.c. Provisional indications
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The majority of attendees proposed the use of provisional approvals, similar to the
approach taken for the approval of drugs under The Minor Use and Minor Species
Animal Health Act of 2004. This would be particularly useful for additional labeling
claims where safety is already determined. Sponsors could collect effectiveness data on
field cases tested under a conditional approval, providing the drug availability for specific
indication sooner, while effectiveness data are still being collected. However, this
approach would require a legislative change, which can be a long and uncertain process.
III. To what extent can pharmacokinetics/pharmacodynamics be used to support a
label indication? What rigor is needed to include PK/PD information on the label? Can
literature­derived PK/PD targets be used?
The appropriate use of PK­PD for a new drug application:
• When there is only a single indication being pursued
• When there are multiple indications being simultaneously pursued
The use of PK­PD to support the addition of claims to previously approved
applications (but within the same target animal species). For this additional
indication, it is assumed that the dose and route (and, therefore, basic PK and
systemic safety) would not be different from the original claim.
The use of PK­PD to support the addition of a related claim in different a species
(e.g., a feline approval for a drug already approved in dogs).
In all cases, PK­PD should be viewed as a tool to reduce clinical field data requirements
to support a drug approval. Situations when PK­PD alone may be used to support a
labeling indication are rare, and primarily involve bridging to existing clinical field safety
and effectiveness data. With the exception of locally acting drugs whose effects are
independent of systemic drug exposure, PK­PD data may answer important therapeutic
questions, potentially allowing sponsors to reduce the size of their clinical field studies.
Assumptions to be established:
When generating PK­PD data, it is essential that sponsors define their foundational
assumptions, provide information to support these assumptions, and indicate what
additional data should be collected. For example, if a drug is from a well­understood
class of antimicrobials, the sponsor could provide existing supporting information to
determine if an antimicrobial acts in a time­dependent or concentration­dependent
manner, and to define the PK­PD targets (e.g., AUC/MIC = X, T>MIC = Y,
Cmax/MIC = Z). Properties of an antimicrobial class may be applied to new drugs of the
same class. However, if a sponsor seeks an indication for substantially different bacteria
from the original indication, or for multiple bacteria, then evidence should be provided to
show that PK­PD criteria apply to all bacteria listed on the indication.

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If a new indication is pursued for a different tissue in the same species, evidence should
be provided that adequate free drug concentrations are obtained in the extracellular tissue
that will support a therapeutic effect. For example, if a drug is already approved for
treating skin infections, and an additional indication is pursued to include bone infections,
respiratory infections, prostate, etc., evidence should be provided to support drug
penetration to those specific new tissue sites at a level similar to or higher than the
original skin infection approval and adequate for a specific PK­PD target. For many
drugs, there may be extensive published data to support assumptions on tissue
partitioning drug characteristics.
Exceptions to traditional assumptions:
There are also situations when assumptions may not be well defined. For example,
multiple studies may be needed to describe the mechanism of action (PD) for novel
drugs. This may be true for newer drugs that work by counteracting bacterial virulence
factors. Another assumption might be to address whether in vitro data adequately reflect
the in vivo drug effect (e.g., does the drug effect involve bacterial killing, bacteriostasis,
anti­inflammatory actions, virulence factors, etc.). Discussions included examples of
where the in vivo tissue environment alters drug activity (in some cases enhanced
activity, in other cases reduced drug activity). Animal models may be a mechanism for
addressing these questions. Discussions also included numerous examples of animals
models being extremely beneficial to the understanding of antimicrobial drug activity
(e.g., neutropenic mouse model, rat thigh model).
For an indication targeted toward organisms for which PK­PD relationships have not
been well­defined (e.g., fastidious organisms, blood borne pathogens), microbiologic data
(e.g., MIC data) and/or PK­PD parameters may not already be established. In such
instances, PK­PD approaches may have limited applicability, and a new indication might
require data from disease models and a clinical field study.
When using a PK­PD approach, there needs to be a solid understanding of the drug
properties, from both a PK and a PD perspective. Critical issues include the presence and
activity of stereoisomers and active metabolites, and the protein binding characteristics.
IV. How can industry partner with veterinary teaching hospitals/referral hospitals to
develop data to support additional indications?
a. Develop common definitions of different disease entities
b. Consortium of data; communication networks for emerging diseases
c. Common treatment modalities
d. How do we measure clinical success when eradication of bacteria is not likely?
(i.e., tick­borne diseases)
e. Certain disease conditions are treated with antimicrobials in conjunction with
other treatments (i.e., pyometra, septicemia, endocarditis, peritonitis). When is it
appropriate to consider adjunctive therapy (an add­on study design)?

One suggested approach:
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Currently, the majority of antimicrobials used in companion animal medicine are not
approved for the indications in which they are commonly used. Most are human­
approved drugs that are used in an extra­label manner in companion animals. Attendees
proposed several disincentives to explain why drug sponsors do not pursue veterinary
drug approvals. Some sponsors questioned the financial incentive to pursuing a drug
approval when the drug is already available for extra­label use by veterinarians.
However, the availability of a properly labeled antimicrobial, including information
supporting the safety and effectiveness of the drug in the approved disease leads to more
judicious use of antimicrobials was presented as the counterargument and a justification
for approval of antimicrobials in companion animals. Other challenges identified include
a lack of standardization in naming and describing disease syndromes. There is also
disagreement among veterinarians as to what constitutes a successful outcome and the
appropriate diagnostic methods to be used for certain diseases. Many participants noted
that veterinary teaching hospitals and referral centers are also financially strapped, and
involved in additional basic and translational research, as well as in teaching students,
which further complicates their ability to conduct field studies for new animal
antimicrobials.
Currently, university teaching hospitals and referral practices have had limited
participation in veterinary field studies. Incorporating them into the companion animal
antimicrobial approval process is increasingly being utilized This limited participation
might be corrected by more effective personnel training in Good Clinical Practice (GCP)
principles and a better understanding of the primary objective of a clinical field study
(e.g., collecting data to support drug effectiveness as opposed to improving the health of
an individual case, although the two objectives are not mutually exclusive). The
negative­controlled study design with an escape clause may be acceptable to IACUC
committees and scientifically more appropriate for establishing drug effectiveness, thus
encouraging university support.
As stated above under Question II, many attendees questioned the possibility of
“conditional” approval, similar to that used in the MUMS Act of 2004, which affords
marketing of an investigational drug in minor species prior to approval, while
accumulating effectiveness data. The potential for the use of surrogate endpoints was
also raised. It was also noted that both of these measures would require legislative
changes. Additionally, it was proposed that limited clinical effectiveness studies in
conjunction with additional information, such as pharmacokinetic studies and other
information (anecdotal, expert opinion) might provide sufficient evidence of drug
effectiveness. The importance of evidence­based medicine was discussed.
Another suggestion included the use of multiple (e.g., five) relevant and adequate peer­
reviewed journal articles to support an additional indication for the same species. The
quality of peer­reviewed journal articles was also discussed and the fact that the study
data used in support of a journal article may not be publicly available.

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When considering study designs for hemoparasite diseases, the difficulties in identifying
the appropriate clinical endpoints of success were discussed. Once veterinary experts
determine the appropriate outcomes of clinical success, then multiple centers might be
able to prospectively enroll cases. Additionally, the use of concurrent medications in
hemoparasite cases should be considered. All current studies allow for an escape clause
so non­responsive cases can be removed from the study for individual health reasons.
Such escape clauses would be necessary if there was a concurrent infection necessitating
additional therapies outside of the proscribed treatment protocol.
Conclusion
In summary of the round­table discussions, which were presented at the end of the
workshop to all the participants, multiple ideas were discussed that could possibly
facilitate the approval path for additional claims for antimicrobial drugs in companion
animals. However, no specific conclusions and agreements were reached during this
meeting; it just opened a door for further discussions between the CVM and drug
sponsors. Both parties welcome continued discussion.