GUEST BLOGGER - JOHN REX
On 1 Mar 2017, FDA hosted an eagerly awaited workshop on animal models in support of narrow-spectrum agents for A. baumannii (Abau) and P. aeruginosa (Pae). It was a full & interesting day at the end of which my confidence that we can plausibly complete acceptable registration programs for narrow-spectrum agents for these two pathogens (and others that are even less frequent) is really improved. (For links to workshops and references – see my notes below).
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:
First, there is an urgent need for new agents for
Pae & Abau. That said, finding agents that cover ONLY Pae or Abau seems
often easier than finding broad agents that also cover them.
Once a candidate is identified, the clinical
development program is very difficult. This was discussed at length last summer and the
problem is that the relative rarity of these infections makes Abau- or Pae-only
agents hard to study at standard statistical strength. There’s been discussion
about using the Animal Rule (aka, Tier D) as an approach, but this
doesn’t seem plausible as Abau and Pae lack the explosive virulence that makes
primate models of plague et al. so compelling in that context. Also, most of
the Animal Rule agents were already approved for other uses.
So, and for new agents, we’re now into the land of
Tier C where we use strong animal models + at least some clinical
data to achieve approval. This is not a path to be pursued unless there is no
other choice, but it is a path we should make available.
And that, then was the point of the 1 Mar discussion.
The essential elements that emerged were that the animal model program would
be some combination of exhaustive PK-PD exploration in smaller animals
(mostly mice) followed by a small number of confirmatory studies in larger
animals (up to and including pigs). The larger animals are intriguing for the
ability to do all the things you see in man – extended infection courses with
substantial life support. Importantly, all models would incorporate internal
controls using humanized exposures of control agents that both should &
should not work.
The clinical program would, simply
put, be as much data as you can generate. Having at least some clinical data
is critical on my levels to making a compelling case both to the ID community
and the payers. As just one motivation for working hard on this, experience in
Europe with Exceptional Circumstances approvals shows that products do
not do well unless such are provided.
As stated above, I see this as a strong step. The next
iteration in this debate appears likely to be the 14-15 June 2017
NIAID-sponsored workshop on PK-PD (no link yet for this – but do mark your
calendar). Exciting times!
All best wishes, --jr
Follow me on Twitter: @JohnRex_NewAbx
1.
There is an
urgent need for new agents for P. aeruginosa (Pae) and A. baumannii
(Abau)
a.
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
a.
Some companies
have made progress by narrowing their focus to JUST Pae & Abau
b.
Compelling
narrow-spectrum candidates vs. both bacteria have now emerged
3.
Frustratingly,
developing an agent limited to one of these pathogens is really hard
b.
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)
c.
These companies
both proposed programs that might (just barely) be feasible
i. But, just barely … and not proven
d.
And, what about Stenotrophomonas
or something else even more rare and difficult?
a) 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:
e.
Tier A: Multiple
standard P3 trials
f.
Tier B: One
standard P3 trial
g.
Tier C: Zero
standard P3 trials but some clinical data
h.
Tier D: No
clinical data except for safety
4.
Tier D (aka, the
animal rule) is not a consistently plausible path. Prior uses of this rule have
depended on
a.
The incredible
virulence of the bacteria (plague, tularemia, anthrax)
b.
The fact that a
very aggressive infection is produced easily with a low inoculum in healthy
animals
c.
The fact that
infection pathogenesis looks a LOT like the infection man
5.
But, Pae and Abau
do not lend themselves to such simple and clear animal models as
a.
Healthy hosts are
often very resistant to infection
i. Hence, we often have to manipulate the host
ii. Degree of mimicry of infection in man is not as high
b.
Not all strains
are equally virulent
6.
So, and
if a clinical trial with standard statistical dimensions is NOT possible, can
we (how can we) lean more on PK-PD?
7.
Q: Can we? A: Yes, provided
a.
We are completely
transparent about why we’re doing this
b.
We make it clear
that stronger clinical data simply are not feasible
c.
We describe the
limits on the overall dataset in the product label
d.
And the community
is suitably cautious about their use
8.
Q: How can we? A: The basis
of approval might thus be (and this is subject to further discussion)
a.
Clear
demonstration of target PK-PD parameters in multiple small animal (mouse)
models – various sites, various strains
b.
(perhaps) some
confirmation of this in a medium-sized animal (rabbit)
c.
And finally
(perhaps) very limited confirmation in a well-standardized large animal model
(e.g., pig)
d.
Across all
models, make use of benchmark control molecules
i. Give humanized exposures with drugs that should /
should not work
ii. Use standard benchmarks to prove the model is
sensitive
e.
And finally,
collect whatever clinical data you can.
i. Statistical interpretation then makes allowance for
the clinical trial limitations
ii. You could think of this as using the animal data to
support a larger alpha or a Bayesian prior
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