Friday, February 25, 2011
Antibiotics - FDA 1, Americans 0
I know that you will all be surprised to hear that I have not had a response from Kathleen Sibelius, nor from the FDA for that matter. I did hear from the FNIH group however. They were upset that I seemed to dismiss their effort before the results were out in the form of docket submissions. Although I remain skeptical, I await further developments and I am truly not dismissive of their efforts – just skeptical and more than a little frustrated. I also recently received a copy of the IDSA submission to the FDA docket on the Draft Guidance on HABP-VABP kindly provided by the IDSA. (The submission does not yet appear on the regulations.gov website so I cannot yet provide a link for you). I am afraid that I once again lashed out in frustration for which I must apologize to IDSA. That said, I am disappointed in their watered-down response to the FDA on the proposed endpoint of 28 day all cause mortality. Here’s what the IDSA says.
IDSA concurs (see our position paper) that, based on currently available data, all-cause mortality is the most appropriate endpoint for a NI HABP/VABP trial. This position is based on the well established effect size of active antibacterial therapy vs. inactive (i.e., “discordant”) therapy for HABP/VABP using a mortality endpoint. Unfortunately, despite active investigation of available datasets and literature, there are very few data currently in the public domain which establish an antibacterial effect size for any non-mortality, clinical endpoint. However, mortality is an insensitive endpoint (i.e., less likely to detect true differences in antibacterial efficacy than clinical endpoints), and clinical response is the preferred endpoint clinically. Therefore, IDSA urges industry and academe to conduct new studies, and reevaluate existing datasets, to establish antibacterial effect size for clinically meaningful endpoints. Upon completion of such analyses in the future, IDSA urges FDA to move rapidly to enable NI studies of HABP/VABP to use clinical primary endpoints.
In my view, the last thing we need is to await more studies before we rescind the use of the mortality endpoint. As noted in a previous blog, the current construction of the trials and called for in the FDA guidance is completely infeasible and should be immediately changed to the more feasible clinical endpoint until such time as some other endpoint is shown to allow for feasible trials. In the meantime, one of our most critical needs for new antibiotics, nosocomial pneumonia, will go without any new development for the foreseeable future at least in the US. Is this what the IDSA wants? Is this what any of us, including the FDA wants?
Why is it so hard to construct trial designs that can be done on planet earth? Why do we feel the need to change an approach that has served us well for the last 20 years? Have we approved ineffective antibiotics?
Europe recently completed its Scientific Advisory Group meeting on antibiotic development. If they go the way of the FDA, we are truly lost. But here I remain optimistic. As long as the US market share for antibiotics continues its inexorable decline and other markets continue to emerge, and as long as there is a way forward to register new antibiotics in these markets via Europe or other regulatory agencies, there is hope – just not for Americans.