Sunday, May 23, 2010

Skin No. 3 - the FNIH

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 (ABSSSI).  Since then, there have been a number of conversations with the agency including my own that I described in a previous blog (  The latest of these took place under the aegis of the Foundation for the NIH.  The reason for this gathering on May 5 was to explore whether there was a need for the NIH to carry out actual developmental work (clinical trials) to help establish the validity of endpoints in the study of complicated skin infections.  I was not invited to the meeting.  But – luckily – I have friends who were invited who provided me with the slides they presented. George Talbot, who organized the meeting, has sent an executive summary that he says is a public document. 

At the meeting, Ed Cox divided the possible process to select endpoints in the study of skin infections into three “Tiers.”  1) Current endpoints are acceptable and no modifications or studies are needed.  2) Development work is still needed but can be “piggybacked” onto ongoing or proposed trials.  3) Development work is required which must be carried out de novo, outside of current trial designs.   It would be within the last category that the NIH might be called into action.

Presentations by John Quinn of Pfizer and Philippe Prockocimer of Trius on trials of linezolid and TR-701 respectively, demonstrated that halting of spread of the lesion occurs in modern trials in a way similar to what was observed in the sulfonamide trials of the 1930s.  The same was actually true of fever, but in modern trials only 10-20% of patients were febrile.  As a biomarker, the lesion of ABSSSI is clearly on the disease pathway since it reflects bacterial multiplication, release of inflammatory factors, etc. and an antibacterial agent’s inhibitory effect on bacterial growth will lead to stabilization and then regression of the lesion. The working group at the meeting reached a consensus that this was both a feasible and desirable endpoint.  It is readily observable, it correlates with ultimate clinical outcome, and it allows for the enrollment of a diverse patient population. They rejected requiring fever for entry into trials since this would not be representative of the population to be treated in the real world and since it would render the trials much less feasible. The working group also recognized the need to ascertain some more sustained response at a later time point.

The FNIH working group will follow up these meetings to discuss a number of remaining questions.  Originally, they were also supposed to have discussed community-acquired pneumonia as well, but they focused on skin during the May 5 meeting.  Follow-up meetings could address pneumonia as well as some remaining questions on skin infections.

This is all interesting, but I wonder if it can possibly have any effect at all on the draft guidance on trial design in skin infections that the agency has said was to appear imminently (around July).  I believe, however, that the FNIH discussion is in line with what the agency will propose in their guidance in any case.  The remaining questions for me, that were not listed in proposed agendas for future FNIH meetings, are; 1) What will the non-inferiority margin be given that the treatment effect of antibiotics on halting the spread of lesion measured at 48-72 hours is well over 30% when compared to UV light treatment which, itself, is more effective than placebo? 2) Will prior antibiotics be proscribed given the potential effect on an early response? (I suspect we can already assume that prior antibiotics will not be allowed). 3) If only cellulitis is studied, in the context of wound infections, ulcers, abscesses, etc., will the label require cellulitis or erysipelas?  How restrictive will the language be and will the FDA force physicians into situations where off-label use is the rule or is very common?  Given a reasonable NI margin, I believe that the trial design as contemplated will be feasible and clinically relevant (thank goodness).  But until the draft guidance appears, we remain in a sort of limbo. 

I understand that the FDA is providing guidance to those companies caught by this reconsideration of design in skin trials, but I have no insight into what this guidance could be.  Forest seems especially vulnerable since they have already completed their pivotal trials and submitted their NDA to the agency. 

As far as I can tell, there has been no substantial progress in the pneumonia discussions.  I do not know where the agency is now in their thinking. I understand from at least one company that the FDA has been very helpful in the design of their trials in pneumonia. As always, for both skin and pneumonia, we await further developments.

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