BreakOut Session Addendum to the October 2008 Antimicrobial ...

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II.a. Additional indication Antimicrobial workshop Breakout session discussion Page 4 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 Antimicrobial workshop Breakout session discussion Page 5 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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