The FDA released its long-awaited Draft Guidance on hospital-acquired pneumonia recently. 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. An editorial in the New York Times noted 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.

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