I was recently invited to participate in another meeting
with the FDA at the Brookings Institution. At the last meeting (summarized in a previous blog) Janet
Woodcock made the extraordinary admission that the FDA would have to reboot in
order to get antibiotic development out of the cellar in the US. Helen Boucher pointed out that this
reboot would have to encompass all aspects of anti-infective development – both
the traditional development pathways where FDA guidance has made development
infeasible as well as identifying new pathways forward to address areas of key
unmet needs for new antibiotics. Both Janet and Helen are right! I am hoping that this reboot will be a
major topic of discussion at the upcoming meeting.
With that in mind, I have recently been considering what a
reboot of the guidance for community acquired pneumonia trials could look
like. Here are my thoughts.
First, rather than jumping into endpoints like symptomatic
response at day 4 as the FNIH and FDA have suggested, lets step back. The justification for this entire step
is to align modern trials with 80-year-old placebo-controlled trials to justify
the NI margin. Of course, even
with a staggering 40% treatment effect, we end up with a margin of just 10% -
how did that happen? FDA magical
discounting – that’s how. But the
clinically relevant endpoint is cure at test of cure – when the patient is sent
home needing no further therapy for their pneumonia. That’s the endpoint that patients and physicians care about
– not whether they are feeling better on day 4 or not. What are the data that these two
endpoints, for any given patient, are well aligned? Lets look at a pharmacometric analysis of the treatment of pneumonia in patients stratified by PORT score and determine the treatment effect in a modern context.
Then there is the issue of prior antibiotics. The FDA says none. This is based on the
famous daptomycin trial.
Daptomycin failed in pneumonia because it is inactivated by
surfactant. Prior antibiotics
masked, but did not completely hide, the inferiority of daptomycin to
ceftriaxone in these trials. The
FDA is putting all their eggs in the daptomycin basket with no confirmatory data. In fact, the data from the ceftaroline
trials might argue that patients with getting prior antibiotics are sicker and
do less well overall than those not receiving them.
But prohibiting all prior antibiotics makes trials
potentially unethical – how can you delay antibiotics for very sick patients
when you know this might increase their risk of mortality? It also makes it
impossible to enroll American patients in trials – but these are the very
patients the FDA wants us to study.
Europe (EMA) says prior antibiotics are OK – but wants
sponsors to try and limit this to a single dose and they want to explore the
effect of the prior antibiotic on the clinical response at the endpoint. Great – FDA – harmonize with Europe!
Then lets explore (that is - it is not a review issue!) the effect of prior
antibiotics in several trials and see where the data lead us.
So here is a potential design for the FDA (and EMA too) –
CABP patients as defined (EMA addendum)
The primary endpoint is clinical outcome at test of
cure. The NI margin is 10% for the
ITT population. One could add the identical endpoint for the microbiologically
documented population with an NI margin of 15% with the population pooled over
two trials as has been recently suggested by the FDA.
A secondary endpoint could be the clinical outcome in
those patients not receiving prior antibiotics with an NI margin of 15%.
Exploratory endpoints could include –
Examine the difference in
clinical outcome both at TOC and at the early 4 day endpoint between no prior
and prior abx – both in control and test arms.
Compare the TOC endpoint
vs. FNIH early endpoint for within patient and overall consistency.
These outcomes can be
explored within the ITT and the microbiological documented populations.
This proposal recognizes the lack of clinical relevance for the early endpoints in community
acquired pneumonia. It also deals with the
infeasibility of prohibiting all prior antibiotics while exploring the effects
of prior antibiotics on non-inferiority studies in this indication. The proposal allows for the development
of oral-only antibiotics by allowing the study of less severely ill patients
for those drugs. Currently, the development of antibiotics available only by the oral route is not possible at the FDA. And the proposal
harmonizes the EMA and FDA guidances overall.
I hope we will be able to discuss this proposal and others
with the agency at the Brookings meeting in August.
I have being researching about bacterial infections and reading your blog. I really appreciate the construction of words in this post.
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