Both the FDA and Salix Pharmaceuticals Inc. will be looking to members of the Gastrointestinal Drugs Advisory Committee Wednesday for answers on designing a clinical trial to demonstrate the safety and efficacy of an antibiotic intended to be used intermittently to treat a chronic condition.

The answers could pave the path forward for Salix's Xifaxan (rifaximin) to become the first antibiotic approved in the U.S. to treat nonconstipation irritable bowel syndrome (IBS).

At the heart of the FDA's questions for the advisory committee is the uniqueness of Xifaxan as an IBS treatment. Drugs already approved to treat IBS have different mechanisms of action, and they were tested continuously during their pivotal trials for a period of about 12 weeks, according to the FDA's briefing documents for the advisory committee meeting.

"The proposed mechanism of action and dosing paradigm for rifaximin . . . presented unique challenges in evaluation of this application," the FDA said.

Salix recognizes the scientific and regulatory hurdles. "Because IBS is considered a heterogeneous condition with no reliable biomarkers, drug development has been challenging, typically rendering a specific product useful in some but not all patients," the company said in its briefing documents.

It noted that some drugs approved for IBS require chronic daily use. Others merely treat the symptoms.

As an antibiotic, Xifaxan may need to be used intermittently, but the two pivotal trials conducted to support approval didn't evaluate the safety and efficacy of retreatment. Subsequently, the FDA wants the committee's input on how to design a trial to establish the safety and efficacy of long-term administration of Xifaxan.

For its part, Salix has come up with a trial design that it thinks will do just that. It wants the committee's feedback on that design. It's proposing a primary endpoint of the proportion of subjects who respond to retreatment in both IBS-related abdominal pain and stool consistency.

The trial design calls for all patients to receive two weeks of treatment and two-weeks of treatment-free follow-up. Responders would go into a treatment-free maintenance phase for at least an additional two weeks. If they have a recurrence, they would immediately be transitioned into a double-blind, randomized retreatment phase that would include two weeks of treatment and two weeks of follow-up. Those who experience a recurrence in a second maintenance phase would receive another repeat treatment.

Salix received a complete response letter earlier this year on its supplemental new drug application (sNDA) for the IBS indication for Xifaxan 550-mg tablets. The drug is already approved to treat traveler's diarrhea and overt hepatic encephalopathy. It also is used off-label in IBS. (See BioWorld Today, Feb. 25, 2011.)

One of the issues the FDA had with that sNDA was Salix's hypothesis that small intestinal bacterial outgrowth were the underlying cause of IBS for the subjects enrolled in the trials. The FDA said the trials were not designed to prove that assumption. And the scientific jury is still out on the root cause of IBS.

Another concern is the potential for developing antibiotic resistance. "If an antibiotic provides marginal clinical improvement, then the potential risk of development of resistance and cross-resistance with other similar drugs (e.g., rifampin) in other bacteria takes on greater weight in the risk/benefit analysis," the agency said.

Currently, the FDA requires stronger clinical trial evidence for antibiotic treatments designed to be used intermittently for a chronic condition than what Salix presented.

As precedence, the agency pointed to its requirements for an antibiotic developed to treat cystic fibrosis-related Pseudomonas aeruginosa infection, which can be life-threatening.

While Salix's trials provided evidence of short-term efficacy, they didn't address retreatment, the FDA said. The pivotal trials had a two-week treatment period, followed by a four-week assessment and then an additional six weeks of monitoring. Overall response was determined to be response for at least two of the four weeks in the assessment period.

Both trials demonstrated a 9 percent to 11 percent improvement over placebo. Salix said data demonstrated the response was sustained for the 12 weeks of the trial, but the FDA said its analysis pointed to a loss of efficacy at weeks six or seven in each trial.

The questions the FDA is asking the advisory committee to weigh in on do not pose a major risk that doctors will sour on Xifaxan as a short-term treatment for IBS, PiperJaffray analyst David Ansellam said.

"Given the dearth of treatment options, even if Xifaxan does not show a benefit in the retreatment context, we still believe usage of the drug will continue to be widespread," he added.

He reiterated an overweight rating and a price target of $51 for Salix (NASDAQ:SLXP).

Despite the optimism, shares of Salix were down $3.66, or 9.8 percent, closing at $33.85 Monday.