The major task confronting FDA and Optimer after an April 5 advisory panel's 13-0 vote in favor of approving the company's Dificid (fidaxomicin) to treat Clostridium difficile will be how to write labeling to communicate the drug's ability to prolong cure to 30 days.

The company is seeking an indication that says the drug can treat C. difficile infection, also known as C. difficile-associated diarrhea, and reduce the risk of recurrence when used for treatment of initial CDI.

FDA's Anti-infective Drugs Advisory Committee unanimously accepted the first half of the claim based on two trials showing non-inferiority to vancomycin, a conclusion supported by FDA (Also see "Fidaxomicin Advisory Committee: FDA Wants Advice On The Meaningfulness Of Infection Recurrence" - Pink Sheet, 1 April, 2011.).

But panel members split 6-6, with one abstention, on the question: "is the finding of lower recurrence of CDAD at Day 31 in the fidaxomicin-treatment subjects of clinical significance?" Christina Surawicz, University of Washington, subsequently said she would change her abstention to a no vote.

Optimer had reported that in the modified intent to treat population, recurrence occurred in 15.7% of patients receiving fidaxomicin and 25.1% of those receiving vancomycin in study 003 and in 12.6% of fidaxomicin patients and 27% of vancomycin patients in study 004.

The firm also presented data showing that fidaxomicin is superior to vancomycin based on a combination of cure at end-of-treatment and no recurrence by the post-study visit (global cure). FDA agreed with this finding but had many qualms about the data on recurrence alone.

In discussing how panel members should interpret the question, Office of Antimicrobial Products Director Edward Cox stressed that their discussion was more important than the actual vote.

In that regard, most members agreed that a discussion in the labeling of the drug's effect through 30 days is appropriate.

Dean Follman, a biostatistician at the National Institute of Allergy and Infectious Diseases, objected to the conclusion that fidaxomicin lowered the risk of recurrence because trial results for this endpoint were not based on patient randomization. Rather, he suggested that the information be presented in terms of a sustained cure or 30-day cure.

"No matter what we call it," this should be part of the information in the label," he said.

Steven Solga, of Solga Gastroenterology, voted yes on the question because "the data do merit some consideration." It may be reasonable to put it in labeling, he said, but putting it into "the actual indication may not be such a great idea."

For Optimer, including the information in labeling supports its plans to position its lead product as first-line treatment for patients considered to be at risk for recurrence, but negotiations with FDA will determine whether it appears upfront as an indication or elsewhere.

Following the meeting, Chief Science Officer Sherwood Gorbach expressed optimism that the company can negotiate language about the drug's 30-day effect in the Indication section.

Optimer has received orphan drug status for fidaxomicin to treat pediatric patients and is discussing a development plan with FDA. The firm proposes to conduct two studies in children two to 18 years of age using vancomycin as the comparator. One study will assess safety and pharmacokinetics; the other will address safety and efficacy

If the antibiotic is approved, Optimer plans to conduct microbiologic and strain testing of 450 isolates per year at six centers and an intervention study in patients with multiple recurrences.

-Cathy Dombrowski (c.dombrowski@elsevier.com )

Communication Of Fidaxomicin's 30-Day Effect Is Question For Labeling Discussions

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