Defending and Dogging the FDA

I know.  You're asking, "Who is writing this blog?"  Its still me.  I'm not schizophrenic yet! But I ran across several news articles regarding the fact that the FDA is insisting that Basilea run two trials to get approval of ceftobiprole, an anti-MRSA cephalsoporin that retains some activity vs. Pseudomonas, for the treatment of hospital-acquired pneumonia instead of the single trial they have submitted.  But that result was entirely predictable as far as I can tell.  The original two trials conducted by J&J and Basilea for complicated skin infection were rejected by the FDA as having been of inadequate quality - essentially - too many mistakes in enrollment and even possible fraud among investigators.  J&J argued that even removing all the questionable enrolling sites, the trial still demonstrated the efficacy and safety of the drug for skin infections, but the FDA stood its ground.  Now - I'm not defending the FDA on this aspect of things. I don't know which argument should prevail here - but a number of really smart people think that J&J proved that ceftobiprole works for skin infections.

But the FDA has said that they will accept a single trial in pneumonia - but it needs to be large - or a single standard (smaller) sized trial when backed by data in another indication.  With the rejection of the data on treatment of skin infections, there are no data to support the single trial in pneumonia presented by Basilea. Also - how big is the safety database?  Can the rejected trials be used to show safety? So where is the surprise here? What were they thinking?  Maybe I'm missing some key information that Basilea can supply. . . .

Now - back to dogging the FDA.  We're still waiting for the FDA to rescind previous infeasible guidance documents,  especially those in both community acquired and hospital acquired pneumonia. I have covered this multiple times in this blog, most recently here.  They are struggling with how to deal with early endpoints that were concocted to conform to their guidance on justifying non-inferiority margins where they had to turn to 80 year old literature that is completely inadequate to determine the treatment effect of sulfonamide antibiotics or penicillin such that our new antibiotics might have a standard for comparison.  But these endpoints are probably not valid, the scientific basis for using the endpoints is questionable at best, and there is no reason to go to these lengths. The FDA has a treasure trove of data on the development of previous antibiotics that can be mined.  They have pharmacokinetic data, the susceptibilities of the pathogens involved and the ultimate clinical outcome of interest - cure at test of cure.  These data can be put together using pharmacometrics to provide a no-treatment level of response and therefore a treatment effect level that can be used to establish a robust justification for non-inferioirty margins using cure as the endpoint. So - where are we?  So far - nowhere.  But I am assured by the FDA that they "are on the case!"  We are all waiting . . . .