FDA Workshop: Animal models in support of narrow-spectrum agents for A. baumannii and P. aeruginosa

Dear All:

FDA today hosted their eagerly awaited workshop on animal models in support of narrow-spectrum agents for A. baumannii (Abau) and P. aeruginosa (Pae). It was a really full & interesting day at the end of which my confidence that we can actually register narrow-spectrum agents for these two pathogens (and others that are even less frequent) is really improved.

We don’t have all the answers, but the basic shape of the answer is apparent and FDA is firmly committed to making it happen. An extended version of what I heard today is found below my signature, but here are the core elements:

1. There is an urgent need for new agents for Pae & Abau
   • Finding agents that cover ONLY Pae or Abau seems often easier than finding broad agents that also cover them
   • But, their relative rarity make Abau- or Pae-only agents hard to study at standard statistical strength
2. Using the Animal Rule (aka, Tier D) isn’t a straightforward path
   • Abau and Pae lack the explosive virulence that makes primate models of plague et al. so compelling
3. So, this is the land of Tier C: Very strong animal models + at least some clinical data
   • It’s not a path to be pursued unless there is no other choice, but it is a path we should make available.
4. The animal model program in support of Tier C? Some combination of
   • Smaller animals (mostly mice): Exhaustive PK-PD exploration
   • Larger animals (up to pigs): A (very) small number of confirmatory studies
   • All models: Internal controls using humanized exposures of control agents that both should & should not work
5. The clinical program in support of a Tier C program? As much data as you can generate
6. The point of all this? Gives the data to make a compelling case both to the ID community and the payers

All best wishes, –jr
Follow me on Twitter: @JohnRex_NewAbx

Extended notes from the 1 Mar 2017 FDA workshop on animal models to support narrow spectrum agents

1. There is an urgent need for new agents for P. aeruginosa (Pae) and A. baumannii (Abau)
   • Infections due these pathogens have high mortality and resistance is real and common
2. But, It’s really hard to find drug candidates that include Pae and Abau
   • Some companies have made progress by narrowing their focus to JUST Pae & Abau
   • Compelling narrow-spectrum candidates vs. both bacteria have now emerged
3. Frustratingly, developing an agent limited to one of these pathogens is really hard
   • An FDA workshop last year (Drug X-1, 18-19 Jul 2016) showed how tough it was
   • Today’s workshop picked up where last summer’s left off and began with presentations on Unmet Need followed by brief reviews of two drug candidates (Polyphor and Entasis)
   • These companies both proposed programs that might (just barely) be feasible. But, just barely … and not proven
4. And, what about Stenotrophomonas or something else even more rare and difficult?
5. So, the workshop today asked what be required of the animal models if want to seriously entertain a Tier C-type data package (Rex JH et al. Lancet ID 13:269-75, 2013) for approval of a new agent:
   • Tier A: Multiple standard P3 trials
   • Tier B: One standard P3 trial
   • Tier C: Zero standard P3 trials but some clinical data
   • Tier D: No clinical data except for safety
6. Tier D (aka, the animal rule) is not a consistently plausible path. Prior uses of this rule have depended on
   • The incredible virulence of the bacteria (plague, tularemia, anthrax)
   • The fact that a very aggressive infection is produced easily with a low inoculum in healthy animals
   • The fact that infection pathogenesis looks a LOT like the infection man
7. But, Pae and Abau do not lend themselves to such simple and clear animal models as
   • Healthy hosts are often very resistant to infection
     • Hence, we often have to manipulate the host
   • Degree of mimicry of infection in man is not as high
   • Not all strains are equally virulent
8. So, and if a clinical trial with standard statistical dimensions is NOT possible, can we (how can we) lean more on PK-PD?
9. Q: Can we? A: Yes, provided
   • We are completely transparent about why we’re doing this
   • We make it clear that stronger clinical data simply are not feasible
   • We describe the limits on the overall dataset in the product label
   • And the community is suitably cautious about their use
10. Q: How can we? A: The basis of approval might thus be (and this is subject to further discussion)
    • Clear demonstration of target PK-PD parameters in multiple small animal (mouse) models – various sites, various strains
    • (perhaps) some confirmation of this in a medium-sized animal (rabbit)
    • And finally (perhaps) very limited confirmation in a well-standardized large animal model (e.g., pig)
    • Across all models, make use of benchmark control molecules
    • Give humanized exposures with drugs that should / should not work
    • Use standard benchmarks to prove the model is sensitive
    • And finally, collect whatever clinical data you can
11. Statistical interpretation then makes allowance for the clinical trial limitations
    • You could think of this as using the animal data to support a larger alpha or a Bayesian prior