BreakOut Session Addendum to the October 2008 Antimicrobial ...

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I.a. A new drug and the first indication Antimicrobial workshop Breakout session discussion Page 2 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
Antimicrobial workshop Breakout session discussion Page 3 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.
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BreakOut Session Addendum to the October 2008 Antimicrobial ...

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