Break Out Session Addendum to the October 2008 Antimicrobial Workshop

Transcription

1 Break Out Session Addendum to the October 2008 Antimicrobial Workshop AAVPT and the United States Pharmacopeia (USP) co sponsored a workshop (October 23 24, 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 two day workshop, there were break out 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 break out sessions, specific scenarios were used to facilitate participation. A summary of the break out session discussions are provided below. This summary provides many individual suggestions, over arching 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. Break Out Session Summary The organizers of the workshop ensured that each break out group included a balanced group of attendees representing veterinary practitioners, the pharmaceutical industry, regulatory agencies and academia. Four thought provoking questions were provided to the break out groups to facilitate discussion. The questions appear below in italics followed by a summary of the suggestions/discussion points from all the break out 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.

2 Page 2 I.a. A new drug and the first indication 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 single site 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 evidence based 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

3 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 post treatment, 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 post treatment 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.

4 II.a. Additional indication Page 4 In general, most break out 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 break out 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 extra label drug use, and for recruiting cases for the preapproval studies. Some attendees cautioned that the down sized 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 multi factorial. 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.

5 II.c. Provisional indications 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 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 literature derived PK/PD targets be used? The appropriate use of PK PD 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 PK PD 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 PK PD 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, PK PD should be viewed as a tool to reduce clinical field data requirements to support a drug approval. Situations when PK PD 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, PK PD data may answer important therapeutic questions, potentially allowing sponsors to reduce the size of their clinical field studies. Assumptions to be established: When generating PK PD 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 well understood class of antimicrobials, the sponsor could provide existing supporting information to determine if an antimicrobial acts in a time dependent or concentration dependent manner, and to define the PK PD targets (e.g., AUC/MIC = X, T>MIC = Y, C max /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 PK PD criteria apply to all bacteria listed on the indication.

6 Page 6 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 PK PD 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, anti inflammatory 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 PK PD relationships have not been well defined (e.g., fastidious organisms, blood borne pathogens), microbiologic data (e.g., MIC data) and/or PK PD parameters may not already be established. In such instances, PK PD approaches may have limited applicability, and a new indication might require data from disease models and a clinical field study. When using a PK PD 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., tick borne 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 add on study design)?

7 Page 7 One suggested approach: Currently, the majority of antimicrobials used in companion animal medicine are not approved for the indications in which they are commonly used. Most are humanapproved drugs that are used in an extra label 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 extra label 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 negative controlled 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 evidence based medicine was discussed. Another suggestion included the use of multiple (e.g., five) relevant and adequate peerreviewed journal articles to support an additional indication for the same species. The quality of peer reviewed journal articles was also discussed and the fact that the study data used in support of a journal article may not be publicly available.

8 Page 8 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 non responsive 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 round table 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.