On December 4 and
5, the FDA is gong to hold back-to-back advisory committee meetings. On Dec 4, the meeting will discuss clinical
development approaches for antibiotics designed for patients with unmet medical
need – in other words, those with serious infections caused by highly resistant
bacterial pathogens. On Dec 5, the
committee will consider the submission by Cerexa/Forest/Actavis for
ceftazidime-avibactam in the treatment of intra-abdominal, urinary tract and
other infections where resistance is problematic. These meetings could be of historical
importance. I won’t have the space to
deal with the Dec 5 meeting preview here –the FDA has not yet released the
background materials for that meeting – more later.
The FDA has
already released background material for the December 4 meeting on the
development of antibiotics for unmet needs. I have read this document and find
myself, once again, disappointed. About half of the document is a historical
review justifying the FDA approach to non-inferiority trials over the last
several decades. They now say they are very satisfied with the outcome of their
labors and are ready to move on to the next thing. Unfortunately, while they may be satisfied
with themselves, I think it is too early to pop the champagne. I can only
conclude that this part of the backgrounder is more for FDA’s political
watchdogs in congress than for anyone truly interested in bringing new
antibiotics to the patients and physicians who need them. While I agree that the
FDA has made significant progress in at least allowing the conduct of clinical
trials that are actually feasible in the real world, the endpoints they have
chosen for these trials still leave much to be desired. I won’t even begin to
talk about the requirement for placebo-controlled trials for sinusitis and
bronchitis – that NO ONE has undertaken since the edict came out around 2003. For
skin infections, the endpoint remains a decrease in the size of the skin lesion
at day 2-3 – not cure. For community-acquired pneumonia it remains symptomatic
relief on day 4 or so – not cure. For hospital-acquired pneumonia it remains
mortality even though about half of the mortality in this disease is completely
unrelated to the infection being treated.
It should be cure of the infection. The situation is still much better
and, in my view, more rational in Europe where cure of the infection remains
the relevant endpoint for all these infections.
But the most
worrisome section of the backgrounder is that dealing with the development of
new agents targeting resistant pathogens – the unmet needs population. A few
highlights (lowlights) that caught my attention are noted below.
1.
A
superiority trial nested within a non-inferiority trial. Actually – this may be
a highlight – I’m not sure. We’ll have
to hear the discussion. But the last
time I was involved (indirectly) with the agency on just such a design, we had
designated a subgroup of the overall population, those with resistant
infections, as an analysis population. Here we were going to look at failure
rates for the control antibiotic and the new drug. We carefully provided for patient safety by
excluding patients with the most serious infections from study entry and by
allowing a rapid switch either to the alternate regime (blinded) or exit from
the study to receive another standard of care antibiotic. The FDA balked at the
design because they didn’t like the subgroup analysis portion. But the backgrounder now indicates that they
would accept such an analysis. Which FDA
is which?
2.
For
superiority trials, they still seem to be laboring under the illusion that head
to head trials are feasible. They’re
not. See my blog
on superiority trials.
3.
As I
noted in that blog on superiority designs, externally controlled trials would
be the most feasible. But the FDA seems at a loss as to how to actually design
such trials. They are harkening back to mortality rates as a preferred endpoint
in externally controlled superiority trials – again – for the most part –
completely infeasible especially in the circumstance they are discussing –
multiple body site infection trials. The FDA seems to recognize the
infeasibility of this approach, but they go on to flounder around about other
possible approaches. I’m worried that
they don’t know what the endpoints should be at the different body sites. (Hint – Cure)!!
a. They suggest the possibility of an
externally controlled non-inferiority design where you could actually show
superiority. This at the very least will
increase trial numbers and expense at a time when we want to do the opposite
and at worst is simply infeasible.
b. They note that there may be disparate
outcomes in different body sites and they give the examples of tigecycline and
doripenem in ventilator-associated pneumonia as examples. Clearly they are
correct – but good human PK/PD work prior to an efficacy trial should be able
to deal with this. Also, as the FDA suggests,
some stratification may be necessary – but this would have to be done in a way
that trial size remains small.
4.
They
also discuss single pathogen trials. Here they seem to rely on rapid diagnostic
approaches that (1) do not really exist and (2) when they are “available” are
not sufficiently rapid. (See my blog
on rapid diagnostics). Clearly, the FDA is still lost here.
5.
Finally,
I will note that in several areas they mention the fatal words “further work.”
The last time they said that, related to trials in skin infections, the
antibiotic pipeline was set back at least 5 years.
I look forward to
listening in on this meeting. I can only
hope that the AIDAC will see some of the same issues that I see and that they
will help sort this out – but my expectations are low.
Now, it just
remains for me to wish all of you in the US a most happy Thanksgiving
holiday. I’ll probably come back to you after
the AIDAC meetings with summaries.
