Tuesday, October 11, 2011
FDA and Pneumonia - Here We Go Again!
The FDA has just announced two days of advisory committee meetings on clinical trial design in pneumonia. November third will cover community-acquired pneumonia and November fourth will cover hospital-acquired and ventilator-associated pneumonia.
For CABP, I think this will be at least the third advisory committee meeting in the last several years and the second since the release of guidance in 2008 requiring infeasible trial designs. The agenda has not been set as far as I know. But the FNIH has submitted comments to the FDA docket focusing on the early endpoints the FDA would like to use for these trials. But the issue of trial infeasibility has not, to my knowledge, been addressed by FNIH officially. The design infeasibility centers around the use of the microbiologically documented population as the analysis population which increases trial numbers by 3-4 fold, making the trials infeasible based on that alone. The other issue, especially in the US, is that with the early endpoints, the FDA is very worried about the effects of even a single dose of antibiotics before enrollment in the trial – so this has been prohibited. But when the emergency room is required to dose antibiotics within 6 hours of presentation for pneumonia as is the case in the US, this constraint rules out enrolling all but a tiny number of Americans in the trials. Even outside the US, the prohibition against any prior antibiotics adds significant additional difficulties to enrolling a trial. The other problem is that, at least as currently stated, for an oral only antibiotic, the NI margin is set a 10% making the patient numbers required astronomical. Some companies have hastily put together an IV program to avoid the trials size requirements for oral only drugs - but even for IV oral drugs, where the NI margin is 15%, the size will be daunting.
The factors leading to infeasibility of the design required for hospital-acquired and ventilator-associated pneumonia are legion and have been well documented in previous blogs.
Will the FDA ask the advisory committee questions around trial feasibility? Will they ask the committee to choose between what they would like to have in a perfect world and what is possible, or will we be once again left with a demand for a scientifically “perfect” trial design which can never be carried out? In my view, these questions are the most important ones and the ones that, in the past, have been almost entirely ignored by the FDA and its advisory committee.
So, you will not be surprised to learn that I have requested time to speak to the advisory committee. My comments will, once again as in the past, be focused on these critical issues of trial feasibility.