Sunday, February 27, 2011

Brad Spellberg Speaks. Antibiotics and the FDA - Present and Future

(Brad and I have been corresponding.  He gave me permission to post this email in hopes of engendering a transparent, public discussion of the issues.   Responses can be placed in comments below or you can send me an email and I will post them.) 

Let’s review the guidances available now, shall we?

Otitis, sinusitis, bronchitis all available—none feasible, these pathways are all closed (requiring superiority).
CABP—guidance available now for 2 years, but guidance irrelevant, debate ongoing including extraordinarily irrational thoughts being frequently mentioned…I agree that this pathway is currently non-viable, and I suspect when the next version comes out I will have to pre-medicate before reading it or risk a stroke.  I believe it will be infeasible and clinically irrelevant when it comes out, given the same people mucking with it as with the skin guidance.

HABP/VABP—guidance available, we’ve discussed. I believe mortality is feasible, but no prior antibiotics is not.  Furthermore, even if “feasible”, I doubt any companies will be willing to enroll several thousand patients at $70,000 per patient in a phase III HABP/VABP protocol for a not very big market in return.  I suspect virtually no non-inferiorirty studies of HABP/VABP will ever be done again, until eventually this is revised.

Skin.  What can I say, I’m not convinced this is viable, and if it is viable, it is certainly clinically irrelevant, and I for one will not prescribe an antibiotic that is approved based on this uninterpretable trial design.  Plus, skin represents the disease for which there is the least medical need.  So, ironically, if skin is viable, it will force even more approval into skin, and away from the other areas of much greater need.

For the future, I believe we have a good sense of what cUTI will look like based on the preliminary “guidance” in the appendix of the Non-Inferiority Trial Guidance.  FDA is actively working on cUTI, and indications are that it will likely be similar to what’s in that appendix.  I’m guessing a margin of 7-10% (10% at MOST, quite possibly smaller).  Probably feasible, but much larger studies than before and quite expensive to do.  Furthermore, the real sticking point is not likely to be the margin or endpoint, but rather FDA’s desire to not allow even a single dose of pre-study antibotics.  My clinical trial group at Harbor-UCLA has agreed to operate phase II cUTI studies from a couple of sponsors at our site.  They haven’t started yet but we’ve been prepping.  We have realized that we cannot capture patients in the ER.  BY then, it will be too late.  A substantial proportion of patients with pyelo or obstructive cUTI are given antibiotics in the triage area before they ever get into the ER.  Furthermore, once in the ER, time to antibiotic is very short.  To have any hope of completing informed consent and all pre-study screening procedures, it will not be possible to capture patients after they’ve already arrived in ER.  This places a tremendous premium on extensive man-power to immediately capture patients on arrival at triage.  So, the studies will be expensive.  Furthermore, the studies will likely require a number of testing procedures that are likely to take an hour or more (such as knowing the creatinine before enrollment). It is likely that many such patients will get treated with antibiotics because they will be febrile and sick and ER docs will not want to wait several hours between first notification of study personnel that a potential patient is there and first giving antibiotics.  I anticipate losing at least 80% of eligible patients to this issue.  I don’t know if large scale studies are feasible or not.  No one does because they’ve never been done.

cIAI, no one knows what will happen here because no HESDE has ever been published.  There is 1 study I’m aware of comparing outcomes in modern IAI patients receiving active vs. inactive antibiotic therapy showing a large point estimate of clinical cure difference.  However, before anyone can comment on feasibility here, the first thing that needs to be done is a systematic literature review for more such data.  I suspect very little else will be found.

So, Dave, that’s where I believe we are.  Mostly infeasible, impossible studies, with a sprinkling of possibly feasible and irrelevant studies and feasible but very hard to do and expensive studies.

Oh boy, the future looks…

1 comment:

  1. These are comments taken directly, with Brad's permission, from our recent email exchanges on the FDA and their current approach to regulating antibiotics.