The FDA released its long-awaited new Draft
Guidance on hospital-acquired pneumonia this week. Their guidance has not
changed since I wrote a blog
about my last meeting with the FDA antibacterial drug development task force
back in September of last year. To reiterate what I stated back then . . .
The FDA position is
that they are unable to identify prior data on the clinical response to
inadequate therapy or no therapy of HAP or VAP in the literature or in previous
antibiotic trials. Therefore, they
cannot assign a treatment effect to antibiotics and therefore they have no
justification of a non-inferiority margin using clinical response endpoints.
Many thought leaders actually agree with this position and further claim that
clinical response is vague and ill defined. So the FDA examined the literature
using both observational studies and previous trials comparing inadequate to
adequate therapy of these infections.
They identified a treatment effect of 42%. Then, of course, they did
their discounting thing to get to an effect of 20% and a proposed margin of
10%.
And, in fact, as the
FDA pointed out during their advisory committee meeting, if you use a different
method to calculate the 10% NI margin – the relative risk method, trial numbers
actually go down as mortality decreases.
In their calculation, at a 15% mortality, which is more typical of
modern trials in HAP/VAP, only 268 patients would be required in each arm given
other reasonable assumptions. This is feasible.
But, if the FDA, statisticians and thought leaders agree on this - should we care?
My belief, in addition
to the problem of feasibility using mortality as an endpoint, is that it is
confounded. That is, many of the deaths
seen in such trials are due to comorbidities and not infection. How many of the deaths we see in such trials
are we talking about? One good study would suggest that there is about 13% overall
mortality attributable to underlying disease and not infection. I have discussed this with Brad Spellberg –
he thinks this is high and he assumes that the real number is closer to 10% or
about 50-67% of the total mortality (15-20% overall) seen in current trials of
HAP/VAP. Statisticians argue that for non-inferiority this is not “confounding”
in their world. In my world, it means
that those deaths – at least half of them, are unrelated to infection, are
irrelevant, and drive the non-inferiority trial conclusion to the null
hypothesis – non-inferiority. I have
never heard a statistician say that this is a good thing (at least until
recently). Brad notes that the trial is
feasible assuming you use the ITT population and not just those with a
bacterial pathogen identified at baseline.
I agree. I also think (and Brad
may agree)– “who cares?”
Even at 268 evaluable patients per arm, given the
disappearing nature of the disease, enrollment might still be challenging. It will certainly remain a very expensive
trial.
I argued that we could easily justify a non-inferiority
margin for clinical response using pharmacometrics to define the treatment
response. The main problem here is that the data set used for the calculations
right now rests on a single trial of tigecycline in ventilator-associated pneumonia. Based on these data, though, in a separate blog
written long ago, I pointed out that the margin under these circumstances
(before a lot of FDA discounting) could easily be 17.5%. But I admit that we
need more robust data. We can obtain the
needed data from contemporary trials of doripenem and levofloxacin in hospital-acquired
and ventilator associated pneumonia. The
FDA could have access to these data easily.
My insistence on this is maybe why they are no longer speaking to me –
who knows?
An interesting example, speaking of irony, is the Astrazeneca
trial of ceftazidime-avibacatam in hospital-acquired pneumonia. In their trial, they have used clinical
response as their primary endpoint and not mortality. They are clearly betting
that their submission will be approved anyway given the importance of this
product to American patients and physicians. I fervently hope that they can get
their act together enough to finish the trial and get the data submitted – but
as you know – it is hard to say what will happen to AZ’s antibiotics programs
right now.
The FDA’s guidance comes out around the same time as the WHO
report on resistance. The editorial
in the New York Times today notes that we need to provide incentives to get
companies back into the antibiotic R&D game to continue to have antibiotics
active against resistant pathogens. We also need realistic regulatory pathways.
While the FDA’s new pathway for hospital acquired pneumonia may be feasible, it
remains, in my view, less than ideal and remains without harmonization with
Europe. Europe is still ahead in this
game as far as I am concerned.
DON’T FORGET THE JOHN
QUINN MEMORIAL FUND.
This comment has been removed by a blog administrator.
ReplyDelete