David's New Book

Friday, December 11, 2009

The FDA, pneumonia and new antibiotics - Progress?

The FDA met with its Anti-infectives Drug Advisory Committee on Dec. 9 to discuss how industry should design clinical trials for new antibiotics to treat pneumonia. It was the clinicians vs. the statisticians and, maybe, just maybe, we all will win. The FDA stated in their summary that infeasible trial designs were unacceptable. PROGRESS! They also showed that, based on clinical grounds alone, antibiotics have an enormous effect on pneumonia by day 3 of illness. Dr. Mary Singer of the FDA showed data from the 1930s through the 1950s demonstrating that, compared to no effective therapy, antibiotics made 30-70% more people significantly better by day 3 of therapy. Of course, every clinician who has ever seen a patient knows this already. One problem will be to better define what "better" means in in 2009.
The advisory committee essentially rejected a call by Public Citizen and others to make mortality the only possible endpoint for clinical trials in pneumonia. Most felt that such trials would not be feasible since they would have to enroll up to 50,000 patients per trial for two trials. In spite of this, the statisticians insisted that mortality was the only scientifically acceptable endpoint.
So - lets make an infeasible trial design which will guarantee that we will have no new drugs for pneumonia in order to achieve perfect science. Let's let the perfect kill the good.
The committee also voted that only those patients where you could show a bacterial pathogen should be evaluated for efficacy in the trial and that patients who had received any prior antibiotic should be excluded from trials. Both of these will still make the design infeasible because of the numbers of patients required and the difficulty of finding patients who have had no antibiotic before they are actually enrolled in the trial.
But I see light at the end of the tunnel. If the FDA would agree to decrease the statistical stringency they require, everything becomes easier. They can justify this scientifically because the effect of antibiotic therapy at day 3 is so great. Then, we need to either be able to pool patients who have a definite bacterial pathogen demonstrated as the cause of their infection across two trials, or we need to be able to use investigational diagnostic tools to increase our diagnosis rates in the trial. If all of this could be done, we can again start to develop new antibiotic for pneumonia. If we can't get most of this done, I'm afraid we will have a long antibiotic drought ahead of us. We will also risk losing more companies who will abandon antibiotic research as simply not providing enough of a return on investment.
Its time for the FDA to realize that NOT having antibiotics effective against resistant pathogens is a SAFETY RISK. Part of their mandate requires that they make sure we have safe and effective drugs. At least for antibiotics where resistance continues to increase, no new antibiotics should not be an acceptable alternative.