FDA and Resistant Infections - the Advisory Committee

Well, today was a big day for the FDA, or not, depending on how you look at things.  The Advisory Committee met to discuss the FDA’s approach to the streamlined development of antibiotics for patients with unmet medical needs – i.e. – those with highly resistant infections where treatment options are limited.  Once again, the makeup of the committee leaves much to be desired.  There are precious few members with expertise in the development of antibacterial drugs in general and in industrial settings in particular.  There are clinicians, statisticians, experts on malaria and on microbiology and pharmacology – but not on the design and execution of clinical trials for antibacterials.  So, my expectations on what would come from the committee per se were low.

The FDA briefing materials also contributed to my low expectations for this meeting.  There was no consideration of the use of pharmacometrics to understand control levels of response in inadequate therapy against which superiority trials of new drugs could be tested. This is in spite of the obvious fact that the FDA is rapidly improving in its ability to understand and manipulate these kinds of data as indicated by the briefing materials for the Cerexa meeting on December 5.

The FDA seemed stuck on active control designs for superiority trials that, according to most industry speakers, will never be feasible.  There was also a good deal of discussion on the use of non-inferiority trials and then an extrapolation from those data plus a large in vitro and PK/PD data base to patients with more rare resistant infections.  This is all good – and we may be stuck with this if the FDA cannot find other ways forward – but what everyone wants is studies in patients with resistant infections.

 

In spite of my expectations, there were some moments where I could see light. There was a clear consensus (except the statisticians) that streamlined trial design is a good idea to allow for the rapid availability of antibiotics for resistant infections to patients and physicians that need them. Things fell apart later when trying to dissect out the details as to how one would do this in practice.

Richard Wunderink and Jeff Alder reminded us how difficult it is to carry out studies in ventilated patients with far less than one patient per center per year being enrolled. The superiority trial for linezolid vs. vancomycin for MRSA VAP took over five years to enroll. Clearly ways to streamline trials in these patients are desperately needed.  But can we get there? There were no clear answers here today. 

Paul Ambrose reminded us all that resistant bacteria are just bacteria.  They follow the same PK/PD rules as susceptible bacteria.  The implication is that with good PK data plus clinical data in susceptible infections – we can be assured that the antibiotics will work in resistant infections.  My only caveat- as noted by some panel members and speakers is that the patient comorbidities may play a confounding role here.

Several speakers emphasized the restrictions on prior antibiotics as being key in preventing trial feasibility because of the impossibility of patent enrollment. While stratifying for prior antibiotics may be good, and stratifying across body sites (pneumonia vs UTI for e.g.) could also be good – these multiple stratifications rapidly lead to increased trial numbers which remain out of reach. I took comfort in the fact that Ed Cox of the FDA in his first sentence (almost) mentioned feasibility before he mentioned scientific rigor.  Maybe there is room for hope here.

The approaches discussed for antibiotics that cover a broad spectrum of pathogens like non-inferiority trials with some extrapolation will not work, though, for those drugs only active against specific pathogens like Acinetobacter or Pseudomonas.  At the end of today’s meeting, I am concerned that there is no clear way forward at FDA for such specifically targeted drugs right now. It looks like the FDA wants to move forward – and if they do – it will be by the seat of their pants on a case by case basis as far as I can see.  But that is better than succumbing to paralysis and not moving at all.