The sponsor's justification for the 10% noninferiority margin relied on historical data related to mortality and "even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure]," the FDA’s briefing documents stated.
There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.
The new end point was not considered a surrogate, "but rather a direct measure of patient well-being," the FDA said.
The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless "provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies."
While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators' recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.
Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.
To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis "provided supportive evidence for the clinical response end point at TOC," the FDA concluded.
Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.
The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.
The FDA's apparent satisfaction with ceftaroline's demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.
Skin & Allergy News Digital Network and "The Pink Sheet" are published by Elsevier.