David's New Book

Thursday, June 17, 2010

Skin No. 4 - The World Turns

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 (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html).  The last chapter involved a gathering on May 5 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 as described in the blog for May 23 (http://antibiotics-theperfectstorm.blogspot.com/2010/05/skin-no-3-fnih.html). 

Yesterday, Trius announced that they had come to an agreement with the FDA on endpoints for their proposed Ph. III trial in skin infections (http://www.triusrx.com/trius-therapeutics-news-100616.php).  They said, “The double-blind pivotal study will compare the efficacy and safety of once-daily oral administration of 200 milligrams of torezolid phosphate over six days of treatment to twice-daily oral administration of 600 milligrams of linezolid (Zyvox) for 10 days of treatment. The primary efficacy endpoint will be the cessation of spread of infected lesions and absence of fever at 48 to 72 hours following initiation of treatment. Secondary endpoints will include, among other things, sustained clinical response at the end of therapy visit, and the investigator’s assessment of clinical response at all visits and clinical success at the post treatment evaluation visit. Provided non-inferiority is met, an assessment of superiority of torezolid phosphate to linezolid with respect to the primary efficacy endpoint will also be made.”  I clarified that the NI margin will not apply to fever, but that patients will have to be afebrile at the 48-72 hour timepoint for the treatment to be considered a success.  Trius and the FDA agreed to a 10% NI margin. Lots of other questions remain regarding the proposed Trius trials such as how the trials will be blinded for example.  Nevertheless,  this is the first indication that the FDA has indeed applied what I believe will be the criteria for their new guidelines for the study of skin infections. 

The NI margin of 10% seems strict given the large treatment effect seen at the 48-72 hour end point. Even with some discounting - this seems excessive for the treatment effect of at least 20-40% compared to not placebo but to UV light which itself is efficacious. 

 This does not clarify what will happen to Paratek who were in the midst of their trials for PTK-0796 or to Forest who have completed their Phase III trials for ceftaroline under the old guidelines for skin infections.  Paratek apparently halted enrollment (see http://www.clintrials.gov) while awaiting new guidance from the agency. 

For companies embarking on programs in skin infections, there seems to be a feasible path forward.  This is nothing but good news for everyone involved in the discovery and development of new antibiotics. Formal guidelines from the FDA are expected sometime this summer.