Skin infections - follow-up.

Sometime in early March, the FDA let it be known through the Infectious Diseases Society and others that they no longer knew how to set a non-inferiority margin for designing trials in serious infections of skin and skin structures.  As I wrote at the time, because this indication is such an important one for the development of antibiotics, this has shaken the world of large pharmaceutical companies, biotechs and investors alike.  Forest Laboratories completed their two pivotal trials of ceftaroline in the treatment of complicated skin infections back in 2008.  If the FDA changes the accepted endpoints or the non-inferiority margin or both at this point, Forest may be obligated to carry out additional costly trials. Paratek announced the initiation of their Ph. III trials in complicated skin infections early in 2009 before their antibiotic was partnered with Novartis. Presumably, these trials are ongoing.  A mid-stream modification, if it occurs, would be costly, but probably better than having to repeat everything.  For those companies who have just completed their ph. II trials and who want to progress their compounds into phase III, they will probably have to wait for the FDA to make up its mind what they want.  Investors waiting to gauge the risk and to see whether further investment is indicated are doing just that – waiting.  In the meantime, company finances are being further strained. For many companies contemplating entering into Ph. II trials, they too are trying to understand how to design these trials such that they will be well positioned to enter phase III when the time comes.  All of this is now in limbo.

I spoke with the FDA this week.  They understand the urgency of the issue.  They believe that they have legitimate concerns around the scientific validity of the traditional endpoints of trials in skin infection – cure at 10-14 days.  The FDA seems to want to tie everything to some 80-year-old placebo-controlled trials so that they clearly understand the treatment effect that, in turn, determines in large part what the statistical margin should be in the design of the trial.  In this regard, they have focused on cellulitis and erysipelas where the 80-year-old data seem to be the most robust.  So it looks like, to register an antibiotic for the treatment of skin infections, there will have to be cellulitis involved.  Wounds will have to have surrounding cellulitis.  Same for abscesses.  There will continue to be significant questions around everything without cellulitis unless we can come up with more placebo-controlled trials to establish a robust treatment effect. This seems highly unlikely at this time.

There are many other ways to approach the question of endpoints other than the 80-year-old endpoints the FDA wants to use.  The other approaches should be a topic of public discussion.  But I fear that this is where we are likely to end up.

In the 80-year-old data, the endpoints examined were early.  The FDA is concerned that antibiotic effect wanes with time of therapy. So our modern endpoints will likely have to be early.  The FDA would like help in refining exactly what those endpoints should be and how they should be measured.  In other words, they would like the NIH or sponsors (guess who will do this better and faster) to incorporate these experimental questions into their phase ii studies. 

During our telecon with the FDA, we discussed the importance of providing a way for companies that have completed trials, have ongoing trials or need to rapidly start trials, to go forward with reduced risk.  The idea is to provide a mechanism for them to bridge to a new endpoint either by a post-hoc analysis if possible or by carrying out a smaller bridging study of phase ii size.  Whether the FDA will agree to this or under what particular circumstances is as yet unclear – but we were not laughed out of the room.

I went into the discussion believing that the FDA lived in some space-time warp where they were the only beings present.  After our discussion, I have a better understanding of their scientific concerns and I even agree that there is a scientific discussion to be had. I still completely disagree with their questioning of whether antibiotics work and how well to the point that they are willing to stop the world turning on its axis while they figure out what we already know.  As the IDSA asks consistently, what ineffective antibiotics have we approved?

I can only hope we can find a way to resolve the urgent issue of allowing clinical development to progress while we address the scientific questions the FDA is posing.