Anyone involved with the development of antibacterial agents will know that animal infection models have always been part of the development process and are essential to demonstrate that a new agent’s in vitro activity translates into in vivo efficacy (a “proof-of-concept” step). However, with the increasing rate of antimicrobial resistance and efforts to develop novel agents to counteract this, the importance of such models is shifting. It is both difficult and expensive to demonstrate clinical efficacy against problematic pathogens, such as multi-drug resistant Acinetobacter species or Pseudomonas aeruginosa, in a clinical trial. However, regulatory approval of a new agent active against pathogens refractory to currently available agents depends on compelling evidence that it will provide clinical benefit. Consequently, there is now much emphasis on developing appropriate animal infection models that can:
- Demonstrate potential utility early in the development process, thereby increasing the likelihood for small biotechs to obtain essential funding to progress the molecule through the development stages, and
- Provide supportive data needed by regulatory authorities to approve a new agent in the absence of conventional clinical efficacy data.
On 5th March 2020, the Food and Drug Administration held a public workshop entitled “Advancing Animal Models for Antibacterial Drug Development" during which, progress and challenges in the development of animal models of serious bacterial infections was discussed. The purpose of the workshop, funded by the FDA, the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA), was to understand the current role animal infection models play in antibacterial drug development and to determine potential priorities for future research and development in this area to assess whether such models could become a validated and integral part of the information database that could support both approval and labelling of a new agent.
Some of the “take-home” messages from this workshop were:
- Mouse models are useful, particularly during the early development stages, but significant issues in “humanizing” the dosing regimens make it difficult to extrapolate efficacy responses from mouse to human.
- Larger animal models, such as rabbit and pig, are being investigated increasingly because they allow both closer approximations of human dosing and the establishment of an infection that more closely relates that seen in humans.
- If animal models could be sufficiently validated, there may be a possibility that evidence from such studies could expand the label beyond those organisms defined as treatable from controlled clinical trial data to encompass the rarer, and more problematic, pathogens that cannot be studied in a clinical trial.
Details of the workshop are available at FDA. Webcast recordings and the meeting transcript are expected to be posted shortly.